scientific directory 2015 - 2019

Transcription

Scientific
D i r e c t o ry
2015 - 2019
Scientific
D i r e c t o ry
2015 - 2019
Gustave Roussy was first created as
the “Institut du Cancer” by Pr. Gustave
Roussy in 1926 and gathers on its campus
around 3,000 professionals, including 239
MD, whose missions are to treat cancer
patients, to set up innovative therapies and
to develop and spread the knowledge within
medical and scientific communities.
The Institute is headed by Pr. Alexander
Eggermont and its specificity is based
on the integration between innovative
healthcare and a top level research through
a tight cooperation with the Université
Paris-Sud and its Faculty of Medicine.
In 2014, the Institute ensured 228,000
medical consultations and hosted 11,800
new patients, 26% of whom have benefited
from an innovative therapy through the
enrollment in one of the 369 ongoing clinical
studies.
Since January 1st 2015, the Chevilly-Larue
hospital (CHSP) has merged with Gustave
Roussy; which increased the total number
of hospital beds up to 435 and of outpatient
units up to 102.
The Gustave Roussy research landscape now
comprises 37 research teams (from basic
science to translational biological research,
from epidemiology and biostatistics to
psycho-oncology and health economy), 14
clinical research teams each focused on
one organ or pathology, a clinical research
division which manages all the aspects of the
clinical research (methodology, biostatistics,
regulatory affairs, operations and
pharmacovigilance), a hospital department
dedicated to therapeutic innovations and
early clinical trials as well as a 10 technology
core facilities brought together within one
administrative “Service Unit”. Research at
Gustave Roussy is coordinated by Pr. Eric
Solary.
In the last years, a global reflection has
been initiated about the evolution of the
technologies core facilities within Gustave
Roussy. As far as genomics is concerned,
Gustave Roussy has externalised the high-
throughput sequencing for the molecular
medicine program (through a partnership
with a biotech company, INTEGRAGEN,
which installed and operates a “clinical
sequencing unit” within the Institute), and
proposes to merge its 2 genomics facilities
(for clinical and basic research) within a
unique facility that can share expertise,
personnel and technology.
The robotised fluorescence videomicroscopic
facility for high-throughput screening
is now available and the creation of a
“pharmacology Platform” for clinical and
basic research is envisioned. Moreover, the
management of the Tumour Bank (~150,000
tumor samples) is being profoundly
modified to give a better access to tumour
samples and to store biological samples
upon prospective research programs.
The Molecular Medicine Program has been
refined by new trial designs with the aim
to answer the question of resistance to
targeted therapies (i.e. MATCH-R) including
sequential biopsies and xenografts.
The Gustave Roussy Immunotherapy
Program (GRIP) has been initiated following
the recruitment of clinical immunologist
who is setting up immunotherapy clinical
trials associated with translational
research.
The onco-haematology program will be
reinforced by the creation of the hospital
haematology department which will give
visibility and coherence to the haematology
clinical activities and foster collaboration
with Gustave Roussy research teams.
early clinical trials, the recruitment of a
senior methodologist specialised in early
phase trial and adaptive designs, and the
coordination of the Institute’s industrial
partnerships.
The present book introduces research groups
and clinical committees currently operating
in Gustave Roussy and the platforms they
use. DNA repair, tumour immunology and
molecular medicine are the three main axes of
basis and translational research, with clinical
research introducing new drugs and testing
biomarkers.
Strengthening international partnerships
Internationally, Gustave Roussy is developing a
program to promote its model of care, to train
foreign professionals, and to improve access
to cancer care for all patients through hospital
projects abroad, which may be one-off or occur
several times a year.
These have taken place in partner countries
such as Kazakhstan, Kuwait and the United
Arab Emirates.
On the research side, the Institute played a key
role in the founding, in July 2014, of “Cancer Core
Europe”, a European comprehensive cancer
center consortium that involves 5 other Cancer
Centres (DKFZ / NCT, VHIO, NKI, Cambridge
Cancer Center, Karolinska Institute). Cancer
Core Europe will make the bridge «bench-tobedside and bedside-to-bench» and conduct
next-generation clinical trials focused on
proof-of-concept, companion, predictive and
resistance monitoring, biomarkers.
Several working groups have been set up,
among which the “IT/ Data Sharing working
group” will develop a common software
platform to integrate all patient data that
federates the databases from each of the
centres. In less than a year, the consortium has
already been successful in two European calls:
TRANSCAN and EIT Health.
Gustave Roussy has drawn its future roadmap
through its Development Program 2015-2020.
Resulting from several months of work by all
the professionals at the Institute, it provides a
framework, based on existing foundations, for
an innovative Comprehensive Cancer Centre.
Within this program, the three main actions
for research are: (i) the creation of clinicianresearchers positions (MD/PhD or PharmaD/
PhD) whose workload will be mainly focused
on ambitious exploratory and/or translational
research projects; (ii) the construction of a
preclinical cancer research facility (PRECAN);
(iii) the creation in 2020 of a renewed Research
Centre endorsed by the National Institutions
(including basic, translational and clinical
research).
This last objective is highly strategic. The
Institute aims at building on an integrated,
first-class, innovative research based on
highly-talented scientists, clinicians and staff
members. After evaluating the potential of
candidate research team leaders, a proposal
for a future research strategy and organisation
of the Research Centre will be discussed, in a
very open system of exchange.
Alexander Eggermont
According to the SAB 2013 recommendations,
several cross-program research projects
are being developed (e.g linking immunology
and DNA repair).
The development of the clinical research
has been mainly focused on early phase
clinical trials through the creation of
the Drug Development department
dedicated to therapeutic innovations and
Director General
Eric Solary
Director of Gustave Roussy Research
RESEARCH KEY NUMBERS from 2012-2014
KEY NUMBERS 2014
Consolidated budget (M€)
100
80
90,1
85,5
70,1
60
40
20
The consolidated budget corresponds to ALL research
expenses for any research activity on Gustave Roussy
Campus, given that these expenses can be incurred
by Gustave Roussy or not (i.e. salaries of the academic
positions, grants that are managed in other institutions, etc.)
0
2012
2013
822,85
879,5
113 PhD students including 41% of non-French PhD students
972,4
800
Research Teams and
technologicals facilities (Others)
600
Clinical Research (GR)
400
Research Teams and
Technological facilities (GR)
200
0
2012
2013
972 Full Time Equivalent (FTE) assigned to the Research Division, including
• 656 FTE employed by Gustave Roussy in the Technological facilities, Clinical Research and Research Teams,
• 316 FTE not employed by Gustave Roussy (Inserm, CNRS, Paris-Saclay University, others) in the Research
Teams and Technological Facilities
2014
Research Workforce (Full Time Equivalent - FTE)
1 000
Research Workforce
6
1
4
4
France
Europe
11
Total Research Manpower
2014
Russia
Asia
1
67
Number of patients included in clinical studies by sponsor
3 690
4 000
3 500
3 000
Latin America
North Africa
19
3 308
India
Middle East
2 813
Academic (except GR)
2 500
Industrials
2 000
Gustave Roussy
1 500
Total
1 000
500
0
2012
2013
Patients included in clinical studies
2014
• 3 308 patients included in clinical studies including 434 patients in early phase clinical trials
• 331 ongoing clinical trial including 86 early phase clinical trials
• 30 % of Gustave Roussy’s new patients included in a clinical study
Number of Publications in peer review journal
1400
1200
1000
Pub IF <10
800
Pub IF>10
600
400
200
0
124
142
180
2012
2013
2014
6
Publications in peer review journal
• 1150 publications in peer review journals
including 180 in journals whose IF>10
A growing part of IF>20
within the total number
of publications
7
Scientific Directory 2015 - 2019
1. RESEARCH TEAMS
Lifestyle, genes and health: integrative trans-generational epidemiology
Marie-Christine Boutron-Ruault P. 33
UMR 981 INSERM: Predictive biomarkers and new molecular
strategies for cancer therapy
Fabrice André P. 17
Methodology and Clinical Epidemiology in Molecular Oncology
Stefan Michiels P. 34
UMR 1170 INSERM: Normal and malignant haematopoiesis
Olivier BernardP. 19
Genetic and Epigenetic control of normal and malignant haematopoiesis
(ATIP-AVENIR)
Camille Lobry P. 20
Radiation Epidemiology, Clinical Epidemiology of cancer and survival
Florent de VathaireP. 35
UMR 9196 CNRS: Molecular physiology and pathology of
infectious and endogenous retroviruses
Thierry Heidmann P. 37
Genetic and modelling of paediatric leukaemia
Thomas MercherP. 21
UMR 8200 CNRS: Genetic stability and oncogenesis
Patricia KannoucheP. 38
Endocytosis, cytoskeleton and cell migration (ATIP-AVENIR)
Guillaume MontagnacP. 22
Cell division and genomic stability
Olivier GavetP. 39
Early steps of haematopoietic transformation
Virginie Penard Lacronique, Olivier Bernard
P. 23
TLS Polymerases and Genome Plasticity
Patricia Kannouche, Said AoufouchiP. 40
haematopoietic stem cells to the differentiation of megakaryocytes
Hana Raslova P. 24
Recombination, Repair, ROS and Cancer
Bernard Lopez, Corinne DupuyP. 41
From haematopoietic stem cell to myelomonocytic differentiation
Eric Solary, Françoise PorteuP. 25
Repair of double strand breaks and genome integrity (ATIP-AVENIR)
Gerard MazonP. 42
UMR 8081 CNRS: Magnetic Resonance Imaging and Multi-Medical Terms (IR4M)
Luc Darrasse
Multimodal imaging in oncology
Nathalie LassauP. 27
UMR 1030 INSERM: Molecular radiotherapy
Eric DeutschP. 29
Tumour Response to Radiation Therapy
Eric Deutsch, Nazanine ModjtahediP. 30
Replication stress, genomic instability and mitosis (ERC Starting Grant)
Valeria NaimP. 43
DNA repair Syndromes
Filippo RosselliP. 44
DNA repair
Murat SaparbaevP. 45
UMR 1138 INSERM: APOPTOSIS, CANCER & IMMUNITY
Guido KroemerP. 47
Cell death and Aging team
Jean-Luc PerfettiniP. 31
UMR 1186 INSERM: Integrative Tumour Immunology
and Genetic Oncology
Fathia Mami-ChouaibP. 49
UMR 1018 INSERM - Centre for Research in Epidemiology and Population
Health (CESP)
Bruno FalissardP. 32
Oncogenesis and tumour progression in melanoma (ATIP-AVENIR)
Mehdi Khaled
P. 50
Integrative Tumour Immunology and Genetic Oncology
Fathia Mami-ChouaibP. 51
2. Clinical Research
EA7348 EHESP – Ecole des Hautes Etudes en Santé Publique
Management of Health Organisation
Etienne MinvielleP. 53
UMR 8203 CNRS: Vectorology and therapeutic anticancer
Lluis MirP. 55
New anticancer therapies
Liliane Massade, Jacques GrillP. 56
Vectorology nucleic acids and anticancer drugs
Luis Mir, Karim BenihoudP. 57
Clinical Research TEAMsP. 72
Genito-Urinary cancer
Laurence Albiges P. 73
Endocrine tumours
Eric BaudinP. 74
Thoracic cancer
Benjamin Besse P. 75
Oncogenetics
Olivier Caron P. 76
Sarcomas
Axel Le Cesne P. 77
UMR 8126 CNRS: signalling, nuclei and innovation in oncology
Joëlle WielsP. 58
Breast cancer
Suzette Delaloge P. 78
Microenvironment, exosomes and microRNAs in solid tumours
Pierre BussonP. 59
Brain tumour
Frédéric DhermainP. 79
Intracellular traffic, macromolecular complexes and cancer
Svetlana DokudovskayaP. 60
paediatric malignancies
Jacques Grill P. 80
Collective invasion (ATIP-AVENIR)
Fanny Jaulin P. 61
Gastro Intestinal cancer
David Malka P. 81
Maintenance of Genomes and Molecular Microscopy
Éric Le CamP. 62
Gynecologic cancer
Patricia PautierP. 82
Proteomics and Epigenetics
Vasily OgryzkoP. 63
Haematological malignancies
Vincent RibragP. 83
Nuclear organisation and pathological models
Yegor Vassetzky / Marc LipinskiP. 64
Dermatology
Caroline Robert P. 84
Oncogenesis and resistance to apoptosis in B lymphoma
Joëlle Wiels P. 65
Head and Neck cancer
Stéphane TemamP. 85
UMR 1015 INSERM: Tumour immunology and immunotherapy
OF CANCER
Laurence ZitvogelP. 67
Psycho-oncology unit
Sarah DauchyP. 86
Role of RNA translation in antigen presentation
Sébastien Apcher P. 68
Regulation of the effector anti-tumour function by dendritic cells
and exosomes: towards the designation
Laurence ZitvogelP. 69
Clinical Research DIVISION
Gilles VassalP. 89
3. core facilities
Biostatistics and epidemiology unit (SBE)
Ellen Benhamou P. 90
CNRS UMS3655 - INSERM US23: MOLECULAR ANALYSIS,
modelling AND IMAGING OF CANCER DISEASE
Jean-Yves ScoazecP. 98
Operations Unit (SORC)
Valérie DejeanP. 91
Pharmacovigilance Unit (UFPV)
Salim LaghouatiP. 92
Clinical Trial Sponsoring Unit (SPEC)
Delphine Vuillier-LegoffP. 93
Immune Monitoring Laboratory in Oncology:
Nathalie Chaput P. 99
Genomics
Nathalie Droin, Ludovic LacroixP. 100
Circulating tumour cells
Françoise FaraceP. 101
Bioinformatics:
Daniel GautheretP. 102
EARLY DRUG DEVELOPMENT DEPARTMENT (DITEP)
Jean-Charles SoriaP. 94
Industrial Partnerships Coordination Committee (CCPI)
Eric AngevinP. 95
Preclinical evaluation platform
Patrick GoninP. 103
Metabolomics
Guido KroemerP. 104
Imaging and cytometry platform
Corinne Laplace-BuilhéP. 105
Proteomics
Vasily OgryzkoP. 106
Biological resource centre:
Jean-Yves Scoazec P. 107
Histopathology
Jean-Yves Scoazec P. 108
UMR 1138 INSERM - DRUG SCREENING platform (PACRI)
Guido KroemerP. 109
R e s e a rc h
teams
UMR 981 INSERM: Predictive biomarkers and new molecular
strategies for cancer therapy
Research Unit director: Fabrice André
Single Team Unit
Details:
Gustave Roussy, Inserm UMR 981,
114, rue Edouard Vaillant, 94805 Villejuif
Tel.: +33(0)1 42 11 56 30
e-mail: Fabrice.ANDRE@gustaveroussy.fr
http://u981.medecinemoleculaire.org/
Team members:
- Permanent researchers: 4 Inserm/CNRS
- Faculty members: 2 Associate Professors
(MCU)
- Technical staff: 6
- Non-permanent researchers: 7 post-docs
- PhD students: 14 (2010-2014)
- Others: 3 University Professor-Hospital
Practitioners
(>20% of time in the Unit) and 6 interns
Keywords
Molecular predictor, clinical
trial, biomarker, translational
research, high throughput biology,
bioinformatics, therapeutic target.
Summary of the research topics:
The aim of the Unit is the identification and validation
of new therapeutic targets and molecular predictors in
oncology. The Unit’s work is based on the principle that
high-throughput molecular characterisation can lead to
the identification of therapeutic targets. The mission is to
transfer the molecular knowledge to clinical practice, and
use patient samples as source of hypotheses for research.
The following elements underlie the principles of the Unit:
a. One of the objectives is the set-up of clinical trials which
test the biomarkers;
b. The Unit can either pilot projects or support other units
performing fundamental research for the transfer of their
concepts;
c. The development of technologies and bioinformatic tools for
translational research is part of the objectives of the Unit;
d. Every project must be co-piloted by a researcher and a clinician.
• 7 patents
• 13 ongoing industrial partnerships
TOP 5 PUBLICATIONS
Dorvault N, Commo F, Adam J, Vanhecke E, Saulnier P, Thomale J, Le Chevalier T, Dunant A,
Rousseau V, Le Teuff G, Brambilla E, Soria JC.
N Engl J Med. 2013 Mar 21;368(12):1101-10.
eIF4F is a nexus of resistance to anti BRAF and anti-MEK cancer therapies.
Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, Thomas
M, Basmadjian C, Ribeiro N, Thuaud F, Mateus C, Routier E, Kamsu-Kom N, Agoussi S,
Eggermont AM, Désaubry L, Robert C, Vagner S.
Nature 2014 Sep 4;513(7516):105-9.
Next-generation sequencing reveals high concordance of recurrent somatic alterations
between primary tumor and metastases from patients with non-small-cell lung cancer.
Vignot S, Frampton GM, Soria JC, Yelensky R, Commo F, Brambilla C, Palmer G, Moro-Sibilot
D, Ross JS, Cronin MT, André F, Stephens PJ, Lazar V, Miller VA, Brambilla E.
J Clin Oncol. 2013 Jun 10;31(17):2167-72.
Comparative genomic hybridisation array and DNA sequencing to direct treatment of
metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).
André F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, Lacroix-Triki M, Lacroix
L, Cohen P, Gentien D, Adélaide J, Dalenc F, Goncalves A, Levy C, Ferrero JM, Bonneterre J,
Lefeuvre C, Jimenez M, Filleron T, Bonnefoi H.
Lancet Oncol. 2014 Mar;15(3):267-74.
Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating
endothelial progenitor cells.
Taylor M, Billiot F, Marty V, Rouffiac V, Cohen P, Tournay E, Opolon P, Louache F, Vassal G,
Laplace-Builhé C, Vielh P, Soria JC, Farace F.
Cancer Discov. 2012 May;2(5):434-49.
ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
Friboulet L, Olaussen KA, Pignon JP, Shepherd FA, Tsao MS, Graziano S, Kratzke R, Douillard
JY, Seymour L, Pirker R, Filipits M, André F, Solary E, Ponsonnailles F, Robin A, Stoclin A,
17
UMR 1170 INSERM: Normal and malignant
haematopoiesis
Research Unit director: Olivier Bernard
Genetic and Epigenetic control of normal and malignant
haematopoiesis (ATIP-AVENIR)
Camille Lobry
Thomas Mercher
Endocytosis cytoskeleton and cell migration
(ATIP-AVENIR)
Guillaume Montagnac
Virginie Penard Lacronique, Olivier Bernard
haematopoietic stem cells to the differentiation of
megakaryocytes
Hana Raslova
From haematopoietic stem cell to myelomonocytic
differentiation
Eric Solary, Françoise Porteu
19
Genetic and Epigenetic control of normal and malignant
haematopoietic (ATIP-AVENIR)
Team leader: Camille Lobry
Team leader: Thomas Mercher
Details:
Details:
Tel.: +33(0)1 42 11
e-mail: Camille.LOBRY@gustaveroussy.fr
Tel.: +33(0)1 42 11 42 33
e-mail: Thomas.MERCHER@Inserm.fr
Team members:
Team members:
- Permanent researchers: 2 Inserm
- Technical staff: 2 (CDD)
- Non-permanent researchers: 1
- PhD students: 3
- Technical staff: 1 Gustave Roussy
- Non-permanent researchers: 1 Inserm
Keywords
Keywords
leukaemia,
epigenetic, stem cells,
lncRNA, Notch
The maintenance of haematopoietic stem cells (HSC) is
a tightly regulated process by transcription factors that
control their self-renewal and commitment to differentiated
blod lineages. A disruption of this process can lead to cell
transformation and leukaemogenesis like Acute Myeloid
Leukemia (AML). We focused our studies on the role of Notch
in early stages of normal haematopoietic and in leukaemia
transformation. Our work suggests that Notch signalling acts
as a tumour suppressor in the AML and agonist molecules of
this pathway could be used in targeted therapy.
Our research projects will focus on two main areas:
-Molecular mechanisms of Notch function in early stages
of haematopoiesis and leukaemic transformation to AML.
-Analysis of the role of long non-coding RNA in the
maintenance of haematopoietic stem cells, their
differentiation and leukemic transformation.
haematology; Oncology;
paediatric leukaemia; Genetic
studies; Fusion oncogenes;
Transcription factors; Functional
modelling; Preclinical studies
by several fusion oncogenes involving transcription
regulators) and acute lymphoblastic leukemia frequently
associated with trisomy 21.
paediatric cancers affect about 1/600 child and represent
the second cause of death in western countries. The
haematological malignancies account for approximately
45% of the paediatric cancers. Clinical features of these
paediatric cancers suggest that they have different bases
compared to the corresponding adult cancers.
We identify the genetic landscape of leukaemia and
perform functional analyses using cellular and preclinical
in vivo models, including transgenic, patient-derived
xenotransplantation and CRISPR-based models.
The overall goal of our studies is to identify the precise
molecular mechanisms of transformation and the bases
for the exclusive association between several genetic
alterations and pediatric cancers in order to develop novel
therapeutic strategies. We primarily focus on paediatric
leukaemia presenting recurrent chromosomal alterations,
including acute megakaryoblastic leukaemia (characterised
The human transcriptome consists of not only coding RNAs
for proteins but also non-coding RNAs. Among these noncoding RNAs, long non-coding RNAs (lncRNA) appear to play
a critical role in controlling the expression of genes involved
in the homeostasis of stem cells. However, their involvement
in the control of HSC and their transformation into AML
remains unexplored. Identifying and characterising such
transcripts could allow design of novel targeted therapies
for this disease.
• 1 ongoing industrial partnership
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Notch signaling: switching an oncogene to a tumor suppressor.
Lobry C, Oh P, Mansour MR, Look AT, Aifantis I.
Blood. 2014 Apr 17;123(16):2451-9.
SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.
Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, Li Y, Chung YR, Micol JB,
Murphy ME, Cho H, Kim MK, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ,
Lobry C, Aifantis I, Modis Y, Allain FH, Halene S, Bradley RK, Abdel-Wahab O.
Cancer Cell. 2015 May 11;27(5):617-30.
In vivo mapping of notch pathway activity in normal and stress hematopoiesis.
Oh P, Lobry C, Gao J, Tikhonova A, Loizou E, Manent J, van Handel B, Ibrahim S, Greve J,
Mikkola H, Artavanis-Tsakonas S, Aifantis I.
Cell Stem Cell. 2013 Aug 1;13(2):190-204
TET1 is a tumor suppressor of hematopoietic malignancy.
Cimmino L, Dawlaty MM, Ndiaye-Lobry D, Yap YS, Bakogianni S, Yu Y, Bhattacharyya S,
Shaknovich R, Geng H, Lobry C, Mullenders J, King B, Trimarchi T, Aranda-Orgilles B, Liu C,
Shen S, Verma AK, Jaenisch R, Aifantis I.
Nat Immunol. 2015 Jun;16(6):653-62.
Gautheret D, Lecluse Y, Landman-Parker J, Radford I, Vainchenker W, Dastugue N, de Botton
S, Dessen P, Bourquin JP, Crispino JD, Ballerini P, Bernard OA, Pflumio F, Mercher T.
J Exp Med. 2012 Oct 22;209(11):2017-31. doi: 10.1084/jem.20121343.
STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a
mouse bone marrow transplantation model.
Couronné L, Scourzic L, Pilati C, Della Valle V, Duffourd Y, Solary E, Vainchenker W, Merlio
JP, Beylot-Barry M, Damm F, Stern MH, Gaulard P, Lamant L, Delabesse E, Merle-Beral H,
Nguyen-Khac F, Fontenay M, Tilly H, Bastard C, Zucman-Rossi J, Bernard OA, Mercher T.
Haematologica. 2013 Jul 19. PubMed PMID: 23872306.
TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a
Recurrent Event during Human Lymphomagenesis.
Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M,
Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P,
Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C*, Mercher T*, Bernard
OA*.
Cancer Cell. 2011 Jul 12;20(1):25-38. PubMed PMID: 21723201. * Co-senior authors
Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH
signaling.
Malinge S, Thiollier C, Chlon TM, Doré LC, Diebold L, Bluteau O, Mabialah V, Vainchenker W,
Dessen P, Winandy S, Mercher T*, Crispino JD*.
Blood. 2013 Jan 18. PMID: 23335373. *Co-corresponding authors
Comments: Maillard I, Blood. 2013 Mar 28;121(13):2376-7. PubMed PMID: 23538229.
Crosstalk between Notch and AKT signaling during murine megakaryocyte lineage
specification.
Cornejo MG, Mabialah V, Sykes SM, Khandan T, Lo Celso C, Lopez C, Rivera-Muñoz P, Rameau
P, Tothova Z, Aster JC, Depinho RA, Scadden DT, Gilliland DG, Mercher T.
Blood. 2011 Jun 7. [Epub ahead of print] PubMed PMID: 21653327.
Characterization of novel genomic alterations and therapeutic approaches using acute
megakaryoblastic leukemia xenograft models.
Thiollier C, Lopez CK, Gerby B, Ignacimouttou C, Poglio S, Duffourd Y, Guégan J, Rivera-Munoz
P, Bluteau O, Mabialah V, Diop M, Wen Q, Petit A, Bauchet AL, Reinhardt D, Bornhauser B,
STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms
dependent on serine phosphorylation.
Gough DJ, Marié IJ, Lobry C, Aifantis I, Levy DE.
Blood. 2014 Oct 2;124(14):2252-61.
20
21
Endocytosis, cytoskeleton and cell migration (ATIP-AVENIR)
Team leader : Guillaume Montagnac
Team leaders: Virginie Penard-Lacronique, Olivier Bernard
Details:
Details:
Tel.: +33(0)1 42 11 56 16
e-mail: Guillaume.MONTAGNAC@gustaveroussy.fr
Tel.: +33(0)1 42 11 42 33 / 52 40
e-mail: Olivier.BERNARD@gustaveroussy.fr ;
e-mail:
Virginie.LACRONIQUE-PENARD@
gustaveroussy.fr
Team members:
- Non-permanent researchers: 2 postdoc Inserm
- PhD students: 1
- Autres: 2 (Gustave Roussy)
Team members:
- Permanent researchers: 4
- Faculty members: 4
- Non-permanent researchers: 4 Post-docs
- PhD students: 5
- Others: 2
Keywords
Cell Biology; Migration
/ invasion; endocytosis;
cytoskeleton; imaging
Endocytosis is a fundamental process that allows the cell to
completely renew its plasma membrane and to internalise
as much as three times its own volume in approximately
one hour. More importantly, endocytosis allows the
internalisation of membrane receptors and their ligands
and thereby controls vital cell functions such as plasma
membrane homeostasis, cell nutrition and intracellular
signalling. All these functions make endocytosis an
essential player in virtually all cell processes including cell
migration, cell division, autophagy and many others.
Our group focuses on the mechanisms underlying cancer
cell migration as well as on fundamental aspects of
endocytosis and microtubules dynamics that directly affect
the capacity of the cell to migrate and survive.
Keywords
stem cell, TET2, IDH, Spi1/PU.1, RhoA,
DNA methylation, splicing, epigenetic,
differentiation, haematopoietic malignancies.
More specifically, we develop projects aiming at analysing
and understanding:
-The role of clathrin-coated pits during cell migration.
-The interplay between actin and microtubule cytoskeletons
and clathrin-coated pits.
-The dynamics of microtubule acetylation
-The dynamics of endocytosis in vivo
The over all aim of our team is to identify the acquired
mutations in the early step of haematopoietic
transformation, understand the network of cooperating
events underlying transformation and develop experimental
models to allow functional investigations and serve as
preclinical models.
We particularly study the connections between endocytosis
and the cytoskeletons at different levels by using
reconstituted in vitro systems, cell culture in 2D and 3D and
intravital analyses. We use a multidisciplinary approach
combining biochemistry, cell biology and biophysics in order
to understand how the cytoskeleton and endocytosis team
up to regulate the different steps of cell migration.
Most of the adult haematological malignancies arise from a
pre-leukaemic phase that involves an infra-clinic expansion
of abnormal, mutated haematopoietic stem/progenitor
cells. It has been shown that genetic lesions in genes
encoding for transcription factors (such as RUNX1, Spi1/
PU.1), mRNA splicing (SF3B1, U2AF35), DNA methylation
(Ten-Eleven-Translocation 2 (TET2), DNA (cytosine-5)methyltransferase 3A (DNMT3A)), intermediate metabolism
(Isocitrate Dehydrogenase 1 and 2 (IDH1/2)) or chromatin
structure (SMC1A) are founding mutations in human
malignancies.
TOP 5 PUBLICATIONS
We are investigating the functional consequences of TET2,
DNMT3A and IDH genetic lesions, that frequently predate
the development of myeloid or lymphoid malignancies
and are involved in epigenetic gene regulation. We are
studying the consequences of alteration in Spi1/PU activity,
a transcriptional factor of the ETS family, which in addition
to transcriptional regulation, plays a role in the control of
epigenetic and RNA splicing regulation. In addition, we are
analysing the roles of the GTPase RhoA and its regulators
(GEFs & GAPs) during normal haematopoietic cell division
and studying how mutations in RhoA may cooperate with
epigenetic factors for lymphocyte transformation.
TOP 5 PUBLICATIONS
Decoupling of activation and effector binding underlies ARF6 priming of fast endocytic
recycling.
Montagnac G, de Forges H, Smythe E, Gueudry C, Romao M, Salamero J, Chavrier P.
Curr Biol. 2011 Apr 12;21(7):574-9.
Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with
GTP for membrane remodeling.
Boissan M, Montagnac G, Shen Q, Griparic L, Guitton J, Romao M, Sauvonnet N, Lagache T,
Lascu I, Raposo G, Desbourdes C, Schlattner U, Lacombe ML, Polo S, van der Bliek AM, Roux
A, Chavrier P.
Science. 2014 Jun 27;344(6191):1510-5.
Abscission accomplished by PtdIns(3)P.
Montagnac G, Chavrier P.
Nat Cell Biol. 2010 Apr;12(4):308-10.
αTAT1 catalyses microtubule acetylation at clathrin-coated pits.
Montagnac G, Meas-Yedid V, Irondelle M, Castro-Castro A, Franco M, Shida T, Nachury MV,
Benmerah A, Olivo-Marin JC, Chavrier P.
Nature. 2013 Oct 24;502(7472):567-70.
ARF6 Interacts with JIP4 to control a motor switch mechanism regulating endosome traffic in
cytokinesis.
Montagnac, G., Sibarita, J.B., Loubery, S., Daviet, L., Romao, M., Raposo, G., and Chavrier, P.
Curr Biol. 2009.19, 184-195.
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K,
Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C,
Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M,
Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE.
Science 2013 May 3;340(6132):622-6.
TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent
event during human lymphomagenesis.
Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M,
Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P,
Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C, Mercher T, Bernard OA.
Cancer Cell 2011;20:25-38.
Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia.
Ridinger-Saison M, Boeva V, Rimmelé P, Kulakovskiy I, Gallais I, Levavasseur B, Paccard C,
Legoix-Né P, Morlé F, Nicolas A, Hupé P, Barillot E, Moreau-Gachelin F, Guillouf C.
Nucleic Acids Res. 2012 Oct;40(18):8927-41
Acquired initiating mutations in early hematopoietic cells of CLL patients.
Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, Diop M, Scourzic L, Shiraishi
Y, Chiba K, Tanaka H, Miyano S, Kikushige Y, Davi F, Lambert J, Gautheret D, Merle-Beral H,
Sutton L, Dessen P, Solary E, Akashi K, Vainchenker W, Mercher T, Droin N, Ogawa S, NguyenKhac F, Bernard OA.
Cancer Discov 2014;4:1088-101.
TET2 and DNMT3A Mutations in Human T-Cell Lymphoma.
Couronne L, Bastard C, Bernard OA.
N Engl J Med 2012;366:95-6.
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
22
23
haematopoietic stem cells to the differentiation
of megakaryocytes
Team leader: Hana Raslova
From haematopoietic stem cell
to myelomonocytic differentiation
Team leaders: Eric Solary, Françoise Porteu
Details:
Details:
Tel.: +33(0)1 42 11 46 71
e-mail: Hana.RASLOVA@gustaveroussy.fr
Tel.: +33(0)1 42 11 42 33
e-mail: Eric.SOLARY@gustaveroussy.fr;
e-mail: Francoise.PORTEU@gustaveroussy.fr
Team members:
Team members:
- Permanent researchers: 4 Inserm, 2 CNRS
- Faculty members: 1, Paris 6
- Technical staff: 1 APHP, 1 Inserm / 1 (CDD)
Gustave Roussy, 1 Inserm, 1 INTS
- Non-permanent researchers: 3 Post-docs
Inserm, 1 Post-doc Gustave Roussy, 1 INTS)
- PhD students : 16 (dont 2 en cotutelle)
- Others: 2 (PH) AP-HP
-Permanent researchers: 4 Inserm, 2 Inserm,
1 CNRS
- Faculty members: 2 PUPH Paris Sud
et Paris 6
- Technical staff: 1 Inserm, 1 CNRS,
1 Inserm, 2 (sur contrats)
- Non-permanent researchers: 2 post-doct
- PhD students: 5
Keywords
Keywords
Megakaryocyte, thrombopenia,
thrombocytosis, MPL, JAK2, Calreticuline,
ontogeny, RUNX1, ANRKD26, cytoskeleton,
myelofibrosis, iPSC
The team N°2 works principally on normal and pathological
megakaryopoiesis. On normal megakaryopoiesis, our
objectives are to better understand the ontogenetic changes,
the role of some transcription factors, the epigenetic changes
and the processes of polyploidisation and platelet formation.
The applications are: i) understanding of platelet toxicity of
some drugs; ii) the development of techniques to produce
platelets in vitro. On pathological megakaryopoiesis, we
studied hereditary diseases including thrombocytopenias
(ex. those associated with mutations in RUNX1 (FPD/AML)
and ANKRD26 (THC2) and thrombocytosis secondary to
mutations in MPL. Their precise mechanisms are studied
in different cell models including iPSC. Myeloproliferative
neoplasms (NMP) are the more important malignancies
studied.
The work is based on the modelling of mutations, especially
JAK2V6217F and calreticulin in various cell models
and in vivo in mice to understand the mechanisms of
transformation and how to target them. Finally the team is
working on predisposition to malignancies characterisedby
mutations in RUNX1, ANKRD26 and by duplication of a new
susceptibility locus for NPM.
• 4 patents
haematopoietic stem and progenitor cells,
Hematopoietic niche, Monocytic lineage, cytokine
receptors, myelomonocytic leukaemias
haematopoietic stem cells (HSCs) in the bone marrow give
rise to all lineages of blood cells in a carefully controlled
equilibrium. An expansion of the myelomonocytic lineage
is associated with inflammation and ageing. A clonal
expansion can also be observed in response to some genetic
and epigenetic alterations of stem or progenitor cells.
response to acute or chronic stresses, either inflammatory
or genotoxic, and in the context of clonal myelomonocytic
leukaemia.
We explore the role of three receptors, CSF1-R, CXCR4, and
MPL in HSC lineage commitment in steady-state and stress
conditions. We also analyse the signalling pathways involved
in terminal monocytic differentiation and polarisation.
Finally, we dissect the pathogenesis of chronic and acute
myelomonocytic leukaemias, using primary cells and
various in vitro / in vivo models.
Chemo/cytokines and the bone marrow niche environment
affect HSC genomic stability, lineage commitment, and
cellular differentiation. The team explores the molecular
mechanisms that drive myelomonocytic expansion in
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.
Manchev VT, Hilpert M, Berrou E, Elaib Z, Aouba A, Boukour S, Souquere S, Pierron G, Rameau
P, Andrews R, Lanza F, Bobe R, Vainchenker W, Rosa JP, Bryckaert M, Debili N, Favier R,
Raslova H.
Blood. 2014 Oct 16;124(16):2554-63.
Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias.
Favier R, Raslova H.
Br J Haematol. 2015 May 5.
Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia.
Antony-Debré I, Manchev VT, Balayn N, Bluteau D, Tomowiak C, Legrand C, Langlois T, Bawa
O, Tosca L, Tachdjian G, Leheup B, Debili N, Plo I, Mills JA, French DL, Weiss MJ, Solary E,
Favier R, Vainchenker W, Raslova H.
Blood. 2015 Feb 5;125(6):930-40.
Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe
bleeding.
Canault M, Ghalloussi D, Grosdidier C, Guinier M, Perret C, Chelghoum N, Germain M, Raslova
H, Peiretti F, Morange PE, Saut N, Pillois X, Nurden AT, Cambien F, Pierres A, van den Berg TK,
Kuijpers TW, Alessi MC, Tregouet DA.
J Exp Med. 2014 Jun 30;211(7):1349-62.
p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic
stress and through the microenvironment during aging.
Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, Villeval JL, Louache F, Gonin
P, Debili N, Plo I, Vainchenker W, Gilles L, Raslova H.
Stem Cell Reports. 2014 Dec 9;3(6):1085-102.
Uzan B, Poglio S, Gerby B, Wu CL, Gross J, Armstrong F, Calvo J, Cahu X, Deswarte C, Dumont
F, Passaro D, Besnard-Guérin C, Leblanc T, Baruchel A, Landman-Parker J, Ballerini P, Baud
V, Ghysdael J, Baleydier F, Porteu F, Pflumio F.
EMBO Mol Med. 2014 Apr 28;6(6):821-34.
Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific
activation of Erk and NF-κB pathways and their target, IEX-1.
de Laval B, Pawlikowska P, Barbieri D, Besnard-Guerin C, Cico A, Kumar R, Gaudry M, Baud
V, Porteu F.
Blood. 2014 Jan 23;123(4):509-19.
Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells
into cancer-associated fibroblasts.
Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P,
Solary E, Berchem G, Moussay E.
Blood. 2015 Jun 22. pii: blood-2014-12-618025.
Characteristic repartition of monocyte subsets as a diagnostic signature of chronic
myelomonocytic leukemia.
Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, Morabito
M, Met E, Debord C, Benayoun E, Nloga AM, Fenaux P, Braun T, Willekens C, Quesnel B,
Adès L, Fontenay M, Rameau P, Droin N, Koscielny S, Solary E; Groupe Francophone des
Myélodysplasies.
Blood. 2015 Jun 4;125(23):3618-26.
Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and
progenitor cell mutagenesis in response to DNA damage.
de Laval B, Pawlikowska P, Petit-Cocault L, Bilhou-Nabera C, Aubin-Houzelstein G, Souyri M,
Pouzoulet F, Gaudry M, Porteu F.
Cell Stem Cell. 2013 Jan 3;12(1):37-48
Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute
leukaemia progression.
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25
UMR 8081 CNRS: Magnetic Resonance Imaging
and Multi-Medical Terms (IR4M)
Research Unit director: Luc Darrasse
Multimodal imaging in oncology
Team leader: Nathalie Lassau
Details:
Gustave Roussy, CNRS UMR 8081, IR4M,
Tel.: +33(0)1 42 11 60 14
e-mail: Nathalie.LASSAU@gustaveroussy.fr
Team members:
- Permanent researchers: 2 CNRS, 1 Gustave
Roussy
- Faculty members: 1 PU-PH
- PhD students: 3
- Others : 4 (doctors)
Keywords
Multimodal imaging, contrast
ultrasound, MRI, photonics,
biomarker validation, Translational
Research, tumor vasculature,
tumour microenvironment
The information specifically provided by all medical imaging
modalities (Ultrasound, CT Scanner, MRI, PET) are many of
them complementary. Consequently, a multimodal approach
is essential to improve diagnosis in oncology. This translates
mainly by advances in the functional characterisation of
tumour and microenvironment, such as temporal resolution
and dynamic studies, characterisation of physical/biological
events, metabolic, cellular and molecular targeting.
conducts translational research programs with a double
objective:
• Development of multimodal imaging tools for clinical &
preclinical approaches in US; MRI and PET-MRI imaging.
• Development of novel characterisation tools for imaging the
tumour microenvironment in an integration of biology imaging
approach.
Moreover, the team has a preclinical ultrasound platform
(Paris-Sud University, FLI) with 4 ultrasound scanners
dedicated to research.
In this context, the team «Multi-modal imaging in Oncology»,
composed of radiologists, researchers and engineers,
TOP 5 PUBLICATIONS
Molecular ultrasound imaging using contrast agents targeting endoglin, vascular endothelial
growth factor receptor 2 and integrin.
Leguerney I, Scoazec JY, Gadot N, Robin N, Pénault-Llorca F, Victorin S, Lassau N.
Ultrasound Med Biol. 2015 Jan;41(1):197-207.
Assessing the response to targeted therapies in renal cell carcinoma: technical insights and
practical considerations.
Bex A, Fournier L, Lassau N, Mulders P, Nathan P, Oyen WJ, Powles T.
Eur Urol. 2014 Apr;65(4):766-77. doi: 10.1016/j.eururo.2013.11.031. Epub 2013 Nov 28. Review.
Dynamic contrast-enhanced ultrasound parametric maps to evaluate intratumoral vascularization.
Pitre-Champagnat S, Leguerney I, Bosq J, Peronneau P, Kiessling F, Calmels L, Coulot J, Lassau
N. Invest Radiol. 2015 Apr;50(4):212-7.
Sorafenib plus dacarbazine in solid tumors: a phase I study with dynamic contrast-enhanced
ultrasonography and genomic analysis of sequential tumor biopsy samples.
Lazar V, Lassau N, Meurice G, Loriot Y, Peña C, Massard C, Robert C, Robert T, Le Berre MA, de
Baere T, Dessen P, Soria JC, Armand JP.
Invest New Drugs. 2014 Apr;32(2):312-22.
Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic
therapy for solid tumors: the French multicenter support for innovative and expensive techniques
study. Lassau N, Bonastre J, Kind M, Vilgrain V, Lacroix J, Cuinet M, Taieb S, Aziza R, Sarran A,
Labbe-Devilliers C, Gallix B, Lucidarme O, Ptak Y, Rocher L, Caquot LM, Chagnon S, Marion D,
Luciani A, Feutray S, Uzan-Augui J, Coiffier B, Benastou B, Koscielny S.
Invest Radiol. 2014 Dec;49(12):794-800.
27
UMR 1030 INSERM: Molecular radiotherapy
Research Unit director: Eric Deutsch
Eric Deutsch, Nazanine Modjtahedi
Jean-Luc Perfettini
29
Team leaders: Eric Deutsch, Nazanine Modjtahedi
Team leader: Jean-Luc Perfettini
Details:
Details:
e-mail: Eric.DEUTSCH@gustaveroussy.fr ;
Tel.: +33(0)1 42 11 49 98
e-mail: nazanine.MODJTAHEDI@gustaveroussy.fr
Tel.: +33 1 42 11 54 91
Tel.: +33(0)1 42 11 65 73 / 54 24
e-mail: Jean-Luc.PERFETTINI@gustaveroussy.fr
Team members:
- Technical staff: 1 Inserm
- Non-permanent researchers: 2 post-doc
- PhD students: 4
Team members:
- Permanent researchers: 4 Gustave Roussy, 1 CNRS, 1 Inserm,
1 Paris-Sud
- Technical staff: 1 Gustave Roussy, 1 Inserm
- PhD students: 5
Keywords
Cell death, Senescence,
Immunity, Radiotherapy
Keywords
Immunity, Metabolism,
tumour microenvironment
and Radiotherapy
translate our research activities from bench to bedside,
we have decided to (a) define and establish molecular and
radiomics signatures of radioresistance, (b) identify cellular
targets for radiosensitation in pre-clinical models, (c) take
advantage of the metabolic reprogramming of radioresistant
tumours for the proposal of new anti-cancer therapies, (d)
classify human tumours with the help of identified molecular
biomarkers, (e) develop diagnostic and prognostic tools
and (f) define personalised therapeutic strategies that will
combine radiation therapy
Recent advances in the understanding of genetic, molecular
and cellular events have highlighted the fact that cancer
is a complex disease of cell types and microenvironments
and urged us to 1) develop an integrative research program
in the field of radiation oncology in order to examine the
complexity of tumour response to ionising radiation (IR) and
2) define novel targets and strategies exploitable in clinic
and 3) develop the next generation radiation oncology.
To reach our objectives, we are developing an ambitious
basic research program that will be organised in 3 axes:
(I) the immune axis, (II) the tumour microenvironment and
metabolism axis and finally, (III) the technology axis. To
Radiation therapy is a cornerstone of cancer management.
After radiation exposure, cells may die through different
modalities of death, ranging from apoptosis and senescence
to autophagy or mitotic death. Despite these knowledge, the
program(s) of death triggered in irradiated cells remain(s)
elusive.
For all these reasons, we decided (i) to further characterise
the molecular basis of IR-induced cell death mechanisms,
(ii) to develop preclinical mouse models to assess the
impact of cell death types on the tumour microenvironment
and on the anti-tumour immune response, (iii) to determine
whether the detection of cell death mechanisms could be
a factor predictive of disease outcome or prognostic for
radiotherapy efficiency and (iv) to identify new technological
approaches that could modulate these cell death programs
and enhance the efficiency of radiotherapy.
Our research work will also address the involvement of cell
death modalities on the “abscopal effect”, analyse crosstalks between micro-environmental cell types and evaluate
the ability of new technologies to enhance (local or distant)
radiation mediated immune responses.
• 4 patents
• 2 spin-off / startups / biotech
• 5 patents
TOP 5 PUBLICATIONS
Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, Mariño G, Kepp O, Michaud M,
Perfettini JL, Kroemer G, Deutsch E.
Cell Death Differ. 2014 Jan;21(1):92-9.
Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.
Hangen E, Féraud O, Lachkar S, Mou H, Doti N, Fimia GM, Lam NV, Zhu C, Godin I, Muller
K, Chatzi A, Nuebel E, Ciccosanti F, Flamant S, Bénit P, Perfettini JL, Sauvat A, BennaceurGriscelli A, Ser-Le Roux K, Gonin P, Tokatlidis K, Rustin P, Piacentini M, Ruvo M, Blomgren K,
Kroemer G, Modjtahedi N.
Mol Cell. 2015 Jun 18;58(6):1001-14.
IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an
opportunity to increase the efficacy of standard therapy.
Ferté C, Loriot Y, Clémenson C, Commo F, Gombos A, Bibault JE, Fumagalli I,Hamama S, Auger N,
Lahon B, Chargari C, Calderaro J, Soria JC, Deutsch E.
Mol Cancer Ther.2013 Jul;12(7):1213-22
Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and
Neck Cancer.
Mondini M, Nizard M, Tran T, Mauge L, Loi M, Clémenson C, Dugue D, Maroun P, Louvet E,
Adam J, Badoual C, Helley D, Dransart E, Johannes L, Vozenin MC, Perfettini JL, Tartour E,
Deutsch E.
Mol Cancer Ther. 2015 Jun;14(6):1336-45.
Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer.
Loriot Y, Mordant P, Dugue D, Geneste O, Gombos A, Opolon P, Guegan J, Perfettini JL, Pierre A,
Berthier LK, Kroemer G, Soria JC, Depil S, Deutsch E.
Cell Death Dis. 2014
Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient
immunogenic signalling.
TOP 5 PUBLICATIONS
Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, Mariño G, Kepp O, Michaud M,
Perfettini JL, Kroemer G, Deutsch E.
Cell Death Differ. 2014 Jan;21(1):92-9.
Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and
Neck Cancer.
Mondini M, Nizard M, Tran T, Mauge L, Loi M, Clémenson C, Dugue D, Maroun P, Louvet E,
Adam J, Badoual C, Helley D, Dransart E, Johannes L, Vozenin MC, Perfettini JL, Tartour E,
Deutsch E.
Mol Cancer Ther. 2015 Jun;14(6):1336-45.
Editorial: Pannexin-1--the hidden gatekeeper for HIV-1.
Paoletti A, Raza SQ, Voisin L, Law F, Caillet M, Martins I, Deutsch E, Perfettini JL.
J Leukoc Biol. 2013 Sep;94(3):390-2.
Entosis, a key player in cancer cell competition.
Kroemer G, Perfettini JL.
Cell Res. 2014 Nov;24(11):1280-1.
Understanding the functions of tumor stroma in resistance to ionizing radiation: emerging
targets for pharmacological modulation.
Chargari C, Clemenson C, Martins I, Perfettini JL, Deutsch E.
Drug Resist Updat. 2013 Feb-Apr;16(1-2):10-21.
Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient
immunogenic signalling.
30
31
UMR 1018 INSERM : Centre for Research in
Epidemiology and Population Health (CESP)
Research Unit director: Bruno Falissard
Lifestyle, genes and health: integrative trans-generational
epidemiology
Team leader: Marie-Christine Boutron-Ruault
Details:
Lifestyle, genes and health: integrative trans-generational epidemiology
Marie-Christine Boutron-Ruault
Gustave Roussy, Team 9, CESP U1018,
Tel.: +33(0)1 42 11 53 86
e-mail: contact@e3n.fr ; contact@e4n.fr
www.e3n.fr ; www.e4n.fr
Stefan Michiels
Team members:
Radiation Epidemiology, Clinical Epidemiology of cancer and survival
Florent de Vathaire
- Research: 17
- Administration: 4
- Databases: 5
- Datamanagement: 7
- Statistics: 4
Keywords
Family cohort, generations,
lifestyle, genetics, epigenetics,
health, cancer, chronic diseases,
prevention, environment
The team’s research is mostly based on the E3N and E4N
cohorts. It investigates the relationships between lifestyle
and the major chronic diseases, with special interest for the
study of the modern way of life in individuals of the same
family, who thus share a genetic background and common
environmental factors.
- To more specifically investigate the associations with
lifestyle, metabolic factors (diet, physical activity), the use
of hormonal treatments, reproductive factors, early life
exposure, etc
- To assess the relationship between chronic diseases and
several biological markers (diet, hormonal milieu, genetic
polymorphisms ...)
- To analyse interactions between genetic characteristics
and potential risk factors
Lines of research
- To analyse the role of environmental and genetic factors,
in the occurrence of and survival after cancer and other
major chronic diseases (diabetes, cardiovascular diseases,
neurological diseases...)
TOP 5 PUBLICATIONS
Association between five lifestyle habits and cancer risk: Results from the E3N cohort.
Dartois L, Fagherazzi G, Boutron-Ruault MC, Mesrine S, Clavel-Chapelon F.
Cancer Prev Res (Phila). 2014 May;7(5):516-25.
Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the
Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l’Education NationaleEuropean Prospective Investigation into Cancer and Nutrition cohort.
Fagherazzi G, Vilier A, Saes Sartorelli D, Lajous M, Balkau B, Clavel-Chapelon F.
Am J Clin Nutr. 2013 Mar;97(3):517-23.
Association between melanocytic nevi and risk of breast diseases: The French E3N prospective
cohort.
Kvaskoff M, Bijon A, Mesrine S, Vilier A, Baglietto L, Fournier A, Clavel-Chapelon F, Dossus L,
Boutron-Ruault MC.
PLoS Med. 2014 Jun 10;11(6):e1001660.
Estrogen-Progestagen Menopausal Hormone Therapy and Breast Cancer: Does Delay From
Menopause Onset to Treatment Initiation Influence Risks?
Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F.
J Clin Oncol. 2009 Nov 1;27(31):5138-43.
Erythrocyte membrane phospholipid fatty acid concentrations and risk of colorectal adenomas :
a case-control nested in the French E3N-EPIC cohort study.
Cottet V, Collin M, Gross AS, Boutron-Ruault MC, Morois S, Clavel-Chapelon F, Chajès V.
Cancer Epidemiol Biomarkers Prev. 2013 Aug;22(8):1417-27.
32
33
Team leader: Stefan Michiels
RADIATION EPIDEMIOLOGY, CLINICAL EPIDEMIOLOGY OF CANCER AND
SURVIVAL
Team leader: Florent de Vathaire
Details:
Details:
Service de Biostatistique et d’Epidémiologie,
Tel.: +33(0)1 42 11 41 44
e-mail: Stefan.MICHIELS@gustaveroussy.fr
Tel.: +33(0)1 42 11 41 40
e-mail: florent.devathaire@gustaveroussy.fr
Team members:
- Permanent researchers : 3
- Technical staff : 11
- Non-permanent researchers : 6
- PhD students : 4
- Others : 2
Team members:
- Permanent researchers: 10, Gustave Roussy
- Faculty members: 3, Univ. Paris-Sud
- PhD students: 5
Keywords
Keywords
Biostatistics – clinical
trials- methodology – clinical
epidemiology – oncology –
biomarkers
The recent revolution in –omics technology and the advent of
targeted therapies have increased the interest in molecular
biomarkers capable of predicting the diagnostic, the clinical
outcome of cancer patients or the response to specific
therapies (diagnostic, prognostic and predictive). There are
many challenges in the appropriate processing of modern
sequencing data and the integration of molecular data in
clinical epidemiology. The development of personalised
medicine implies the segmentation of common cancers
in small groups of tumours with specific abnormalities. A
new generation of clinical trial designs requiring repeated
biomarker measurements and surrogate clinical endpoints
is needed to evaluate treatment effects in trials with limited
sample sizes. Large-scale collaborative individual patient
data meta-analyses are useful tools to provide high level of
evidence on the efficacy and toxicity of anti-cancer therapies
in molecularly defined strata. With the increasing number
of therapies available for a specific indication in oncology,
methods for network meta-analyses will be developed to
compare their effectiveness. Because of the high costs
associated with the new tandem diagnostic and therapeutic
medicine, economic analyses will be needed to evaluate the
strategy associating the biomarkers with the molecularly
targeted treatments, which represents a new field of
research. Once a potential biomarker has been identified for
the prediction of diagnosis or clinical outcome of patients,
evidence-based evaluation implies careful replication in
other cohorts.
Epidemiology;
biostatistics; radiation
dose; cancer; iatrogenic
effect; genetic; cohort
The team works on cancer epidemiology, with a focus on the
effects of ionising radiation and iatrogenic effects of long-term
cancer treatments. The implantation of the team in Gustave
Roussy allows a close collaboration with the departments of
radiotherapy, medical physics, nuclear medicine and paediatrics,
and a unique position to carry out translational research.
Since many years, the team has been following cohorts of subjects
exposed to different dose levels of ionising radiation, including
cohorts of cancer survivors. Over the last years, the study of the
long-term outcome of patients treated for cancer, especially
in childhood, has been one of the main fields of research of
the team. This work requires estimating accurately the doses
received in and outside of the fields during radiation therapy,
which is possible thanks to the software specifically developed
by the team, and working on statistical methodological issues to
better evaluate iatrogenic effects of long-term cancer treatments.
Within the next years, the team will go further into its current
research topics and develop new ones. Descriptive epidemiology
of tobacco, alcohol, and cancer screening is now a part of the
research field of the team. With the arrival of sociologists in the
team, the social consequences of late effects of cancer treatments
will also be addressed. The team is also developing projects on
genetics, in cancer aetiology and in the study of long-term effects.
In this framework, strengthening the collaboration with biologists,
radiation therapists and clinicians, especially paediatricians,
remains a key point in going further, and into developing innovative
translational research projects.
• 2 patents
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled
analysis of individual patient data
Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali
D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF,
De Mattos-Arruda L, Ignatiadis M, Lebofsky R, van Laere SJ, Meier-Stiegen F, Sandri MT,
Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson SJ, Raimondi C,
Rutten A, Janni W, Munzone E, Carañana V, Agelaki S, Almici C, Dirix L, Solomayer EF, Zorzino
L, Johannes H, Reis-Filho JS, Pantel K, Pierga JY, Michiels S.
Lancet Oncol. 2014;15(4):406-14
Dose finding with longitudinal data: simpler models, richer outcomes.
Paoletti X, Doussau A, Ezzalfani M, Rizzo E, Thiébaut R.
Stat Med. 2015 Jun 24
Cost effectiveness of molecular profiling for adjuvant decision making in patients with nodenegative breast cancer.
Bonastre J, Marguet S, Lueza B, Michiels S, Delaloge S, Saghatchian M.
J Clin Oncol. 2014;32(31):3513-9.
Preoperative chemotherapy for non-small-cell lung cancer : a systematic review and metaanalysis of individual participant data.
NSCLC Meta-analysis Collaborative Group.
Lancet. 2014;383(9928):1561-71
Dose-Finding Designs using a novel Quasi-Continuous Endpoint for Multiple Toxicities.
Ezzalfani M, Zohar S, Qin R, Mandrekar, Le Deley MC.
Stat Med. 2013;32(16):2728-46.
34
Ovarian reserve after treatment with alkylating agents during childhood.
Thomas-Teinturier C, Allodji RS, Svetlova E, Frey MA, Oberlin O, Millischer AE, Epelboin S,
Decanter C, Pacquement H, Tabone MD, Sudour-Bonnange H, Baruchel A, Lahlou N, De
Vathaire F.
Hum Reprod. 2015 Jun;30(6):1437-46.
Functional data analysis in NTCP modeling: a new method to explore the radiation dosevolume effects.
Benadjaoud MA, Blanchard P, Schwartz B, Champoudry J, Bouaita R, Lefkopoulos D, Deutsch
E, Diallo I, Cardot H, de Vathaire F.
Int J Radiat Oncol Biol Phys. 2014;90:654-63.
Common variants at 9q22.33, 14q13.3, and ATM loci, and risk of differentiated thyroid cancer in
the French Polynesian population.
Maillard S, Damiola F, Clero E, Pertesi M, Robinot N, Rachédi F, Boissin JL, Sebbag J, Shan L,
Bost-Bezeaud F, Petitdidier P, Doyon F, Xhaard C, Rubino C, Blanché H, Drozdovitch V, Lesueur
F, de Vathaire F.
PLoS One. 2015 Apr 7;10(4):e0123700.
Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a
retrospective cohort study.
de Vathaire F, El-Fayech C, Ben Ayed FF, Haddy N, Guibout C, Winter D, Thomas-Teinturier C,
Veres C, Jackson A, Pacquement H, Schlumberger M, Hawkins M, Diallo I, Oberlin O.
Lancet Oncol. 2012;13:1002-10.
Repair of ionizing radiation-induced DNA damage and risk of second cancer in childhood
cancer survivors.
Haddy N, Tartier L, Koscielny S, Adjadj E, Rubino C, Brugières L, Pacquement H, Diallo I, de
Vathaire F, Averbeck D, Hall J, Benhamou S.
Carcinogenesis. 2014;35:1745-9.
35
UMR 9196 CNRS:
Molecular physiology and pathology of
infectious and endogenous retroviruses
Research Unit director: Thierry Heidmann
Single Team Unit
Details:
Gustave Roussy, CNRS UMR 9196,
Tel. office: +33(0)1 42 11 54 33
e-mail: Thierry.HEIDMANN@gustaveroussy.fr
Team members:
- Permanent researchers: 3 CNRS, 2 Inserm
- Technical staff: 6 CNRS
- Non-permanent researchers: 5 post doc
- PhD students: 3
Keywords
retrovirus, endogenous retrovirus, envelope
protein, cell-cell fusion, immunosuppression,
placentation, tumorigenesis, therapeutic
molecules, vaccines
• Summary of the research topics :
3) characterisation of the immunosuppressive
(IS) domain of retroviral envelope proteins (ERVs,
oncoretroviruses, lentiviruses) ; demonstration of their
critical role for viral penetrance ; characterisation of
the molecular and cellular targets of the IS domain
and search for inhibitors to develop new therapeutic
molecules
1) Molecular retrovirology : characterisation of
endogenous retroviruses, identification of functional
copies and of the cellular receptors ; physiopathology of
the human endogenous retrovirus type K (HERV-K) ; role
in tumorigenesis
2) Endogenous retroviral envelope genes : identification
and characterisation of « syncytins »,
captured genes involved in placentation : demonstration
of their role in syncytiotrophoblast formation via knockout
mice, identification of independently captured genes
among the major clades of placental mammals ; role in
myoblast fusion and muscle fiber formation
4) Developement of « improved » vaccine antigens
deprived of immunosuppressive activity: application to
a anti-FeLV veterinary vaccine (marketed mid-2012) ;
development of HIV and HTLV optimised antigens, and of
vectorised vaccines for pre-clinical and clinical assays
• 4 patents (2 with license)
• 1 start-up
TOP 5 PUBLICATIONS
Retroviral envelope gene captures and syncytin exaptation for a placental function in
marsupials.
Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, Catzeflis F, Nilsson M, Pierron G,
Heidmann O, Zeller U, Dupressoir A, Heidmann T.
Proc. Natl. Acad. Sci. USA, 2015, 112, E487-496.
Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for
placentation in the primitive Afrotherian tenrecs.
Cornelis G, Vernochet C, Malicorne S, Souquere S, Tzika AC, Goodman SM, Catzeflis F,
Robinson TJ, Milinkovitch MC, Pierron G, Heidmann O, Dupressoir A, Heidmann T.
Proc Natl Acad Sci U S A, 2014, 111, E4332-41
A targeted mutation within the FeLV envelope protein immunosuppressive domain to improve a
canarypox-based FeLV vaccine.
Schlecht-Louf G, Mangeney M, El-Garch H, Lacombe V, Poulet H, and Heidmann T.
J Virol. 2014, 88, 992-1001.
Retrovirus infection in vivo requires an immune escape virulence factor encrypted in the
envelope protein of oncoretroviruses.
Schlecht-Louf, G., Renard, M., Mangeney, M., Letzelter, C., Richaud, A., Ducos, B., Bouallaga, I.,
and Heidmann, T.
Proc. Natl. Acad. Sci. USA, 2010, 107, 3782-87.
The HERV-K human endogenous retrovirus envelope protein antagonises Tetherin antiviral
activity.
Lemaître C, Harper F, Pierron G, Heidmann T, Dewannieux M.
J Virol. 2014, 88, 13626-37.
36
37
UMR 8200 CNRS: Genetic stability and oncogenesis
Research Unit director: Patricia Kannouche
Team leader: Olivier Gavet
Olivier Gavet
Details:
Tel.: +33(0)1 42 11 62 25
e-mail: Olivier.GAVET@gustaveroussy.fr
Patricia Kannouche, Said Aoufouchi
Team members:
- Faculty members: 1 - Université Pierre et
Marie Curie, Paris (UPMC)
- Technical staff: To be recruited
- PhD students: 1 (UPMC)
Bernard Lopez, Corinne Dupuy
Repair of double strand breaks and genome integrity (ATIPAVENIR)
Gerard Mazon
Keywords
Kinase, Phosphatase, Cell
division, Cancer, Signalling
pathways, Biosensors
Replication stress, genomic instability and mitosis (ERC
Starting Grants)
Valeria Naim
DNA REPAIR SYNDROMES
Filippo Rosselli
Conversely, MEN inactivates DNA damage signalling around
mitotic entry. Thus, entry into mitosis is finely tuned by an
equilibrium between opposite signaling pathways. How this
dynamic equilibrium is modulated in space and time during
G2/M progression remains poorly characterized and is the
main focus of our work.
A common hallmark of cancer cells is the appearance of
genetic abnormalities whose progressive accumulation
correlates with disease «aggressiveness». The main focus
of our lab is to determine how is timely and reproducibly
controlled mitotic commitment during any cell cycle to
preserve genomic integrity.
DNA repair
Murat Saparbaev
To decipher the spatio-temporal regulation of key
components of MEN versus DDR pathways we are currently
combining genetically encoded FRET (Förster Resonance
Energy Transfer) biosensors and real time live cell imaging
assays.
Entry into mitosis is tightly controlled by a complex
signalling network (Mitotic Entry Network or MEN), which
ultimates in the activation of Cyclin B1-Cdk1, the master
mitotic driver. DNA damages responses (DDR) modulate
this network at different levels to control entry into mitosis.
• 1 patent
TOP 5 PUBLICATIONS
Deciphering the spatio-temporal regulation of entry and progression through mitosis.
Gheghiani L, Gavet O.
Biotechnol J. 2014 Feb;9(2):213-23.
Dynamic changes in Rap1 activity are required for cell retraction and spreading during mitosis.
Dao VT, Dupuy AG, Gavet O, Caron E, de Gunzburg J.
J Cell Sci. 2009 Aug 15;122(Pt 16):2996-3004.
Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis.
Gavet O, Pines J.
Dev Cell. 2010 Apr 20;18(4):533-43.
Centrin4p, a novel mammalian centrin specifically expressed in ciliated cells.
Gavet O, Alvarez C, Gaspar P, Bornens M.
Mol Biol Cell. 2003 May;14(5):1818-34. Epub 2003 Feb 6.
Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis.
Gavet O, Pines J.
J Cell Biol. 2010 Apr 19;189(2):247-59.
38
39
- TLS Polymerases and Cancer - Group leader: Patricia Kannouche
- Genome Plasticity and B cells - Group leader: Said Aoufouchi
- Recombination, Repair and Cancer - Group leader: Bernard Lopez
- ROS and radiocarcinogenesis - Group leader: Corinne Dupuy
Details:
Details:
Tel.: +33(0)1 42 11 40 30
e-mail: Patricia.KANNOUCHE@gustaveroussy.fr ;
e-mail: Said.AOUFOUCHI@gustaveroussy.fr
Tel.: +33(0)1 42 11 63 25
e-mail: Bernard.LOPEZ@gustaveroussy.fr
e-mail: corinne.DUPUY@gustaveroussy.fr
Team members:
Team members:
Group1:
TLS Polymerases and Cancer
- Permanent researchers :
1 CNRS, 1 CNRS (emeritus)
- Technical staff : 1 CNRS
- Non-permanent researchers :
1 post-doc
- PhD students : 2 PhD students,
Paris-Sud
Group 1: Recombination,
Repair, ROS and Cancer
- Permanent researchers:
2 (CNRS)
- PhD students: 1
Group2 : Genome Plasticity and B cells
- Permanent researchers :
1 Inserm
- Faculty members : 1 Paris-Sud
- Technical staff : 1 Paris-Sud
Keywords
DNA repair, Double strand break repair,
Homologous recombination, Non-homologous
end-joining, replication stress, oxidative
stress, genome instability, tumor initiation,
NADPH oxidases, Thyroid cancer and fibrosis
Keywords
TLS polymerase, DNA replication,
heterochromatin, xeroderma
pigmentosum, lymphomas,
immunoglobulin gene diversification, AID
Translesion synthesis Process: a trade-off between limited
mutagenesis and chromosomal instability (group1)
Bulky lesions in the DNA can cause arrest of replicative
polymerases. Failure to relieve such DNA replication stress can
have dire consequences for the cell, as stalled replication forks
are prone to collapse and could potentially lead to double-strand
breaks (DSBs) that result to gross chromosomal instability
that have a close link to tumorigenesis. Cells have evolved
DNA damage tolerance strategies enabling the replication
machinery to bypass fork-blocking lesions. One DDT pathway,
the translesion synthesis (TLS) entails specialized low-fidelity
polymerases, which can replicate damaged DNA, albeit in
an error-prone manner. Therefore TLS has a conflicting
role in genome stability maintenance, as it accounts for a
large proportion of DNA damage-induced mutagenesis but
prevents even more severe forms of genome instability such as
chromosome rearrangements.
In addition to their roles in the replication of damaged DNA, TLS
polymerases have been co-opted into a number of other related
processes. During development of the immune response, the
antibody genes of vertebrates exhibit a particularly high rate of
focused mutagenesis, known as somatic hypermutation, which
is driven by activation-induced deaminase (AID). Although AID
can only deaminate dC to dU, its action gives rise to mutations
at all four bases in a series of reactions that crucially depend
on the Y-family polymerases. The dU formed by the action of
AID is removed by uracil DNA glycosylase (UNG), resulting in an
abasic site. Direct replication of this abasic site involves REV1
and generates mutations at dG-dC base pairs. Recognition of
dU can also result in the formation of a single-strand gap, and
the filling of these gaps by polη results in mutations at dA–dT
base pairs.
One important question emerges from these different roles of
TLS polymerases: How TLS polymerases are regulated and
integrated with DNA replication, repair, epigenetic maintenance
and chromatin architecture in mammalian cells? Detailed
insight into these processes is highly topical for improving new
concepts into cancer development and treatment.
Boosting the mutagenesis: Somatic hypermutation during
Immunoglobulin diversification (group2)
Group 2: ROS and radiocarcinogenesis
- Technical staff : 1 Assitant ingénieur
(AI, CDD CNRS)
- PhD students: 2
Group 1: Recombination, Repair, and Cancer
DNA double strand breaks (DSB) are highly toxic lesions
that can be produced by ionizing radiation, oxidative stress
or DNA replication accidents.
Group 2: ROS and radiocarcinogenesis
Despite much progress in order to improve the benefit
/ risk ratio, the radiation causes many side effects. One
consequence of side effects is an increased risk of initiation
of new cancers such as thyroid cancer and the development
of fibrosis. Basically, late effects of ionizing radiation involve
reactive oxygen species (ROS). In cells, ROS are specifically
produced by NADPH oxidases (NOX/DUOX). The thyroid
expresses three of them. By producing ROS, the NADPH
oxidases are suspected to be involved in genetic instability
as well as in fibrogenesis process. With cellular and animal
models and state-of-the-art technology, our objective is to
dissect the molecular and mechanistic events from postirradiation (IR)-induced ROS generation to genomic instability
and radiocarcinogenesis as well as to fibrosis. During the last
five years we developed transversal studies focused on thyroid
oncogenesis and therapeutics, encompassing basic research
(Corinne Dupuy), translational and clinical research (Martin
Schlumberger, PU-PH, Director of the School of Cancer).
DSB can then generate genetic instability and thus can be
at the origin of oncogenesis, senescence and developmental
diseases.
Two main processes repair DSBs: Homologous
recombination (HR) and Non-homologous End Joining
(NHEJ).
Our research projects analyze the molecular and metabolic
networks controlling DSB repair in mammals and the
orientation of the repair toward one or the other pathway,
and the consequences on genome stability, tumor initiation
and progression.
• 4 patents
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Aberrant C-terminal domain of polymerase η targets the functional enzyme to the proteosomal
degradation pathway.
Ahmed-Seghir S, Pouvelle C, Despras E, Cordonnier A, Sarasin A, Kannouche PL.
DNA Repair (Amst). 2015 May;29:154-65.
Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch
recombination junctions in mouse B cells.
Nguyen TV, Riou L, Aoufouchi S, Rosselli F.
J Exp Med. 2014 Jun 2;211(6):1011-8.
The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome
stability.
Guervilly JH, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, Despras E, Kuraoka I,
Kannouche P, Rosselli F, Gaillard PH.
Mol Cell. 2015 Jan 8;57(1):123-37.
Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients
reveals 12 new disease-causing POLH mutations.
Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert
C, Kannouche P, Soufir N, Sarasin A.
Hum Mutat. 2014 Jan;35(1):117-28.
Proteomic analysis reveals a FANCA-modulated neddylation pathway involved in CXCR5
membrane targeting and cell mobility.
Renaudin X, Guervilly JH, Aoufouchi S, Rosselli F.
J Cell Sci. 2014 Aug 15;127(Pt 16):3546-54.
Spontaneous slow replication fork progression elicits mitosis alterations in homologous
recombination-deficient mammalian cells.
The cohesin complex prevents the end-joining of distant DNA double-strand ends.
Camille Gelot, Josée Guirouilh-Barbat, Tangui Le Guen, Elodie Dardillac, Catherine Chailleux,
Yvan Canitrot and Bernard S. Lopez ().
Mol Cell, Volume 61, Issue 1, p15–26, 7 January 2016
Therese Wilhelm, Indiana Magdalou, Aurélia Barascu, Hervé Técher, Michelle Debatisse and
Bernard S. Lopez
Proc Natl. Acad. Sci. USA. 2014, 111.763-768.
NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure
to irradiation.
Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart JM,
De Deken X, Miot F, Diallo I, de Vathaire F, Schlumberger M, Dupuy C.
Proc Natl Acad Sci U S A. 2015; 112(16):5051-6.
A role for BLM in double strand break repair pathway choice: prevention of CtIP/Mre11mediated alternative non-homologous end-joining.
Anastazja Grabarz, Josée Guirouilh-Barbat, Aurelia Barascu, Gaëlle Pennarun, Diane Genet,
Emilie Rass, Susanne M. Germann, Pascale Bertrand, Ian D. Hickson and Bernard S. Lopez.
Cell Reports, 2013, 5, 21-28.
When an Intramolecular Disulfide Bridge Governs the Interaction of DUOX2 with Its Partner
DUOXA2.Carré A, Louzada RA, Fortunato RS, Ameziane-El-Hassani R, Morand S, Ogryzko V, de
Carvalho DP, Grasberger H, Leto TL, Dupuy C
Antioxid Redox Signal. 2015 23(9):724-33
40
41
Repair of double strand breaks and genome integrity
(ATIP-AVENIR)
Team leader: Gerard Mazon
Replication stress, genomic instability and mitosis
(ERC Starting Grants)
Team leader: Valeria Naim
Details:
Tel.: +33(0)1 42 11 42 11 extension 38 76
e-mail: Gerard.MAZON@gustaveroussy.fr
Details:
Tel.: +33(0)1 42 11 63 33
e-mail: Valeria.NAIM@gustaveroussy.fr
Team members:
- Technical staff: 1 Gustave Roussy (CDD)
- Non-permanent researchers: 2 CNRS (CDD)
Team members:
- Non-permanent researchers: 1 CNRS
- PhD students: 1
Keywords
Homologous Recombination,
Double-strand break, Resolvases,
Crossovers, Translocations,
Chromosome Segregation defects
Double strand-break (DSB) repair is a critical pathway
for genome integrity.
Chromosome rearrangements
(chromosome los, duplications, translocations...) and
genomic aberrations occur in the absence of DSB repair or
due to its incorrect repair. Homologous recombination (HR)
is a multi-step pathway of critical importance for the DSB
repair, but the way these multiple steps of HR are regulated
is still unknown in detail, specially for the late recombination
steps where there exist the risk of the formation of crossing
over products that exchange genetic information between
the chromosomes involved, with potential risk for loss
heterozygosity and translocation formation.
The project of our team aims to better understand the
regulation of the diferent players involved in the “crossing
over” formation during DSB repair, using both yeast and
human cell lines as models. The yeast model allows us to
look at molecular intermediates at a level we still are unable
to work in human cell lines. We draft phenotypes from
mutations on regulation motifs on the different helicases
and nucleases involved in crossover formation in the yeast
model and then test them in the human homologs to see
their relevance for the DSB repair process in a more relevant
context for cancer research.
Keywords
genomic instability, DNA replication
stress, DNA damage, chromosomal
instability, fragile sites, mitosis, Fanconi
anaemia, chromosome segregation.
Our team is interested in the mechanisms of genome
maintenance and the role of replication stress in genomic
instability and cancer predisposition.
Alterations at CFS loci are commonly found in tumours and
promote genomic instability from the early steps of cancer
development.
Our research project aims at understanding the molecular
causes and the functional consequences of CFS instability,
using FA cellular and mouse models.
The model of study is Fanconi anaemia (FA), a genetic
disorder characterised by chromosome instability, bone
marrow failure and cancer predisposition.
Patients with FA display chromosomal instability, particularly
at common fragile sites (CFS), genomic regions that are
prone to breakage under replication stress conditions.
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
The Rad1-Rad10 nuclease promotes chromosome translocations between dispersed repeats.
Mazón G, Lam AF, Ho CK, Kupiec M, Symington LS.
Nat Struct Mol Biol. 2012 Sep;19(9):964-71.
Ethylene oxide and propylene oxide derived N7-alkylguanine adducts are bypassed accurately
in vivo.
Philippin G, Cadet J, Gasparutto D, Mazon G, Fuchs RP.
DNA Repair (Amst). 2014 Oct;22:133-6.
Monitoring bypass of single replication-blocking lesions by damage avoidance in the
Escherichia coli chromosome.
Pagès V, Mazón G, Naiman K, Philippin G, Fuchs RP.
Nucleic Acids Res. 2012 Oct;40(18):9036-43
The Cdk/cDc14 module controls activation of the Yen1 holliday junction resolvase to promote
genome stability.
Eissler CL, Mazón G, Powers BL, Savinov SN, Symington LS, Hall MC.
Mol Cell. 2014 Apr 10;54(1):80-93.
Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates.
Mazón G, Symington LS.
Mol Cell. 2013 Oct 10;52(1):63-74.
ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication
intermediates at common fragile sites during mitosis.
Naim V, Wilhelm T, Debatisse M, Rosselli F.
Nat Cell Biol. 2013 Aug;15(8):1008-15
The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and
genome stability.
Mol Cell. 2015 Jan 8;57(1):123-37.
DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in
mitosis.
Bergoglio V, Boyer AS, Walsh E, Naim V, Legube G, Lee MY, Rey L, Rosselli F, Cazaux C, Eckert
KA, Hoffmann JS.
J Cell Biol. 2013 Apr 29;201(3):395-408.
Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation
defects, palmoplantar keratoderma and skin carcinoma.
Courcet JB, Elalaoui SC, Duplomb L, Tajir M, Rivière JB, Thevenon J, Gigot N, Marle N, Aral B,
Duffourd Y, Sarasin A, Naim V, Courcet-Degrolard E, Aubriot-Lorton MH, Martin L, Abrid JE,
Thauvin C, Sefiani A, Vabres P, Faivre L.
Eur J Hum Genet. 2015 Jul;23(7):957-62.
Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice.
Pawlikowska P, Fouchet P, Vainchenker W, Rosselli F, Naim V.
Blood. 2014 Dec 4;124(24):3613-23.
42
43
DNA REPAIR SYNDROMES
Team leader: Filippo Rosselli
DNA repair
Team leader: Murat Saparbaev
Details:
Details:
Tel.: +33(0)1 42 11 51 16
e-mail: Filippo.ROSSELLI@gustaveroussy.fr
Tel.: +33(0)1 42 11 54 04
e-mail: Murat.SAPARBAEV@gustaveroussy.fr
Team members:
Team members:
- Permanent researchers: 1 CNRS,
- Faculty members: 1 Paris-Sud
- PhD students: 2
- Others: 1 PR Emérite Paris Sud
- PhD students: 3
Keywords
Base excision repair, Nucleotide incision repair,
oxidative DNA damage, interstrand crosslinks,
AP endonuclease, DNA glycosylase, active DNA
demethylation, acquired resistant to anticancer
therapy, crystal structure of DNA repair complex.
Keywords
DNA repair, mitosis,
Recombination, replication,
Fanconi anaemia, cancer
predisposition
Our strategy will follow three axes to:
Characterise at molecular and cellular level the DNA
damage response (DDR) through the keyhole of the FANC/
BRCA pathway.
Identify the functions of the FANC pathway outside the DDR,
to obtain a global understanding of the FA phenotype to
better support patients care.
Understand the role(s) of the FANC pathway in both
differentiation and cancer, the physiological and pathological
faces of the cell behaviour.
The ambition of the research’s projects that will be
developed in the team over the coming years is: a) to
achieve an improved understanding of the cellular and
molecular mechanisms activated in response to genotoxic
stress together with a better characterisation of the cellular
fonctions of the FANC/BRCA pathway and its integration
in the DNA damage response network; b) to precisely
define its physiologic role(s) in healthy cells, tissues and
individuals; c) to determine how its inactivation participate
to cancer intiation and progression. Our goals span, indeed,
from basic to translational research, fully integrating the
scientific strategies and objectives of CNRS and Gustave
Roussy Institute.
DNA damage which include bulky adducts, interstrand
crosslinks (ICLs) and clustered lesions. Although, the repair
pathways for simple non-bulky oxidative DNA damage are
well established, the detailed molecular mechanisms of
the removal of complex DNA lesions in mammalian cells
remains poorly understood.
The main research interest of the group is the field of DNA
repair and mutagenesis, particularly in the various aspects
of the enzymology of the repair of oxidative DNA damage
and active DNA demethylation in mammalian cells. DNA is
constantly subjected to chemical modifications endogenous
and exogenous agents that induce frequently base and
sugar lesions of different types, which are quickly repaired
in vivo.
Our research aims to identify, at the molecular level, a
relationship between a failure in DNA repair and genetic
instability either at nucleotide (substitution, modification,
insertion or deletion) or chromosome (genetic and
epigenetic) level. One might think, that the origin of the agerelated degenerative diseases is related to such defects in
the cell.
The clinical features of inherited human DNA repair
deficient disorders such as Cockayne syndrome and Fanconi
anaemia point to complex nature of endogenous oxidative
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and
genome stability.
Mol Cell. 2015 Jan 8;57(1):123-37.
ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication
intermediates at common fragile sites during mitosis.
Naim V, Wilhelm T, Debatisse M, Rosselli F.
Nat Cell Biol. 2013 Aug;15(8):1008-15.
Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch
recombination junctions in mouse B cells.
Nguyen TV, Riou L, Aoufouchi S, Rosselli F.
J Exp Med. 2014 Jun 2;211(6):1011-8.
The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and
chromosome abnormalities.
V. Naim and F. Rosselli.
Nature Cell Biology, 11, 761-768, 2009.
Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice.
Pawlikowska P, Fouchet P, Vainchenker W, Rosselli F, Naim V.
Blood. 2014 Dec 4;124(24):3613-23.
44
Functional variants of human APE1 rescue the DNA repair defects of the yeast AP
endonuclease/3’-diesterase-deficient strain.
Wang Z, Ayoub E, Mazouzi A, Grin I, Ishchenko AA, Fan J, Yang X, Harihar T, Saparbaev M,
Ramotar D.
DNA Repair (Amst). 2014 Oct;22:53-66.
Characterization of DNA substrate specificities of apurinic/apyrimidinic endonucleases from
Mycobacterium tuberculosis.
Abeldenov S, Talhaoui I, Zharkov DO, Ishchenko AA, Ramanculov E, Saparbaev M, Khassenov B.
DNA Repair (Amst). 2015 May 22;33:1-16.
Oxidatively Generated Guanine(C8)-Thymine(N3) Intrastrand Cross-links in Double-stranded
DNA Are Repaired by Base Excision Repair Pathways.
Talhaoui I, Shafirovich V, Liu Z, Saint-Pierre C, Akishev Z, Matkarimov BT, Gasparutto D,
Geacintov NE, Saparbaev M.
J Biol Chem. 2015 Jun 5;290(23):14610-7.
Pre-steady-state fluorescence analysis of damaged DNA transfer from human DNA
glycosylases to AP endonuclease APE1.
Kuznetsova AA, Kuznetsov NA, Ishchenko AA, Saparbaev MK, Fedorova OS.
Biochim Biophys Acta. 2014 Oct;1840(10):3042-51.
Conformational Dynamics of DNA Repair by Escherichia coli Endonuclease III.
Kuznetsov NA, Kladova OA, Kuznetsova AA, Ishchenko AA, Saparbaev MK, Zharkov DO,
Fedorova OS.
J Biol Chem. 2015 Jun 5;290(23):14338-49.
45
UMR 1138 INSERM: APOPTOSIS, CANCER & IMMUNITY
Research Unit director: Guido Kroemer
Single Team Unit
Details:
Centre de Recherche des Cordeliers,
Inserm UMR 1138, 15 rue de l’Ecole de
Médecine, 75006 Paris
Tel.: +33(0)1 42 11 60 41
e-mail: Kroemer@orange.fr
Team members:
- Permanent researchers : 5 Inserm
- Faculty members : 2
- Technical staff : 3 Inserm, 2 Gustave Roussy, 3
University, 1 CNRS, 2 others
- PhD students : 11
- Others : 1
Keywords
apoptosis, non-apoptotic
cell death, immunity
Since years, we have been working on the pathophysiological
impact of apoptosis and non-apoptotic cell death modalities
including autophagic cell death, necroptosis, necrosis
depending on mitochondrial permeability transition, and mitotic
catastrophe. We are currentlycharacterising the stress pathways
(including autophagy, unfolded protein response, mitochondrial
stress...) that are elicited by cytotoxic chemotherapeutics,
targeted anticancer agents and caloric restriction mimetics.
We aim at identifying the molecular links between damage
to cellular organelles, intracellular stress responses and
extracellular danger signals that stimulate inflammatory and
immune reactions. For this, we are studying danger signals that
appear on the surface of stressed cell or that are released as
soluble factors. We are also identifying the pattern recognition
receptors that are stimulated by such danger signals, as well
as the innate immune effectors and lymphocyte subpopulations
involved in the response against dead-cell antigens.
• 7 patents
TOP 5 PUBLICATIONS
Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigenpresenting cells.
Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, Portela Catani JP, Hannani D,
Duret H, … Van Endert P, Solary E, Smyth MJ, Zitvogel L, Kroemer G.
Immunity. 2013 Apr 18;38(4):729-41
Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in
mice.
Michaud M, Martin I, Sukkuwala A, Adjemian S, Ma Y, Pellegati P, Shen S, Kepp O, Scoazec M,
Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, Galluzzi L,
di Virgilio F, Zitvogel L, Kroemer G.
Science. 2011 Dec16;334:1573-1577
An immunosurveillance mechanism controls cancer cell ploidy.
Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, Galluzzi L, Adjemian S, Kepp O,
Niso-Santano M, Shen S, Mariño G, Criollo A, Boilève A, Job B, Ladoire S, Ghiringhelli F, Sistigu
A, Yamazaki T, Rello-Varona S, Locher C, Poirier-Colame V, Talbot M, Valent A, Berardinelli F,
Antoccia A, Ciccosanti F, Fimia GM, Piacentini M, Fueyo A, Messina NL, Li M, Chan CJ, Sigl V,
Pourcher G, Ruckenstuhl C, Carmona-Gutierrez D, Lazar V, Penninger JM, Madeo F, LópezOtín C, Smyth MJ, Zitvogel L, Castedo M, Kroemer G.
Science. 2012 Sep 28;337(6102):1678-84.
46
47
Regulation of autophagy by cytosolic acetyl coenzyme A.
Marino G, Pietrocola F, Eisenberg T, Malik SA, Fuchs A, Schroeder S, Pendl T. Harger A,
Niso-Santano M, Zamzami N, Scoazek M, Enot D, Martins I, Senovilla L, Morselli E, Vacchelli E,
Bennetzen M, Magnes C, Sinner F, Pieber T, Maiuri C, Andersen JS, Madeo F, Kroemer G.
Mol Cell 6;53(6):710–725.
Metabolic control of cell death.
Green DR, Galluzzi L, Kroemer G.
Science 2014 Sep 19;345(6203):1250256.
UMR 1186 INSERM: Integrative Tumour
Immunology and Genetic Oncology
Research Unit director: Fathia Mami-Chouaib
ATIP-AVENIR - Oncogenesis and tumour progression in melanoma
Mehdi Khaled
Fathia Mami-Chouaib
49
Oncogenesis and tumour progression in melanoma (ATIP-AVENIR)
Team leader: Mehdi Khaled
Research Unit director: Fathia Mami-Chouaib
Deputy Research Unit director: Salem Chouaib
Details:
Details:
Gustave Roussy, Inserm UMR 1186, 114, rue
Edouard Vaillant, 94805 Villejuif
Tel.: +33(0)1 42 11 37 67
e-mail: Mehdi.KHALED@gustaveroussy.fr
Tel.: +33(0)1 42 11 48 52 / 49 65
e-mail: Fathia.Mami-Chouaib@gustaveroussy.fr
Team members:
Team members:
- Technical staff: 2 Gustave Roussy, 1/2 Inserm
- Non-permanent researchers: 1 (CDD,
Inserm)
- PhD students: 1
- Faculty members: 3 EPHE
- Technical staff: 4 Inserm, 2 Gustave Roussy, 1 EPHE
- PhD students: 6
- Others: 8 PH et PU-PH
Keywords
Keywords
Melanoma, metastasis,
therapeutic targets
Melanomas arise from epidermal cells called melanocytes.
Altough the proportion of melanoma is only around 1% of
all skin cancers, it is responsible for ~75% of skin cancer
deaths. The deadliness of melanoma is linked to their high
metastatic potential; and once they disseminate, there is
no efficient treatment. Hence it is crucial to understand in
detail the mechanisms involved in metastasis to improve
actual treatment. Using different approaches, our lab
strives to identify genes driving the early steps of melanoma
progression to discover new therapeutic targets
- Immunology, Immunotherapy, Genetics,
- Lung cancer, melanoma, hereditary kidney cancer,
- CTL, CD103, hypoxia, EMT, von Hippel-Lindau (VHL)
mutations
concentrated on:
1) Investigate the nontranscriptional function of p53 in the
regulation of cell death and its role in cancer-associated
fibroblasts (CAF); 2) Elucidate the impact of hypoxic stress on
tumour plasticity and immune heterogeneity, and understand
the interaction between MITF and hypoxia in the control of
melanoma progression and
3) Develop a translational research around the anti-leukaemic
potential of NK cells in AML patients and the identification of
biomarkers of melanoma progression.
Our INSERM unit U1186 will focus mainly on lung cancer,
melanoma and Renal Cell Carcinoma (RCC). Our project will
be articulated around 3 main themes developed by 3 groups
with the aim of integrating tumour immunology and tumour
biology in the future innovative immunotherapy approaches and
targeted therapies.
Theme 1: “tumour antigens and T-cell reactivity”. Leader: fathia
Mami-Chouaib. The program of this group aims to:
1) Further investigate the role of CD103 in regulating intratumour T-cell migration and effector functions as well as
integrin signalling pathways;
2) Elucidate the influence of guidance molecules, including
semaphorins and their receptors, on T-cell recruitment within
lung tumour islets and
3) Develop a novel cancer vaccine approach in lung cancer based
on the preprocalcitonin (ppCT) tumor antigen.
Theme 3: “genetics and biology of renal cell carcinoma”. Leader:
Stéphane Richard. The research project of this group aims at:
1) Searching new mutated genes responsible for unexplained
familial RCC syndromes by next generation sequencing on
germline DNA;
2) Understanding the physiopathology of inherited RCC using a
functional genetic approach and
3) characterising genomic profiles of hereditary and sporadic
RCC.
Theme 2: “impact of tumour microenvironment on tumour
resistance and its role in shaping tumour plasticity and stroma
reactivity”. Leader: Salem Chouaib. The activity of this group is
• 2 spin-off / startups / biotech
• 2 patents
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Yokoyama S, Scott KL, Garraway LA, Song JS, Granter SR, Turley SJ, Fisher DE, Novina CD.
Mol Cell. 2010 Dec 10;40(5):841-9.
Transcription factor/microRNA axis blocks melanoma invasion program by miR-211 targeting
NUAK1.
Bell RE, Khaled M, Netanely D, Schubert S, Golan T, Buxbaum A, Janas MM, Postolsky B,
Goldberg MS, Shamir R, Levy C.
J Invest Dermatol. 2014 Feb;134(2):441-51.
Control of melanocyte differentiation by a MITF-PDE4D3 homeostatic circuit.
Khaled M, Levy C, Fisher DE.
Genes Dev. 2010 Oct 15;24(20):2276-81.
Feed-forward microprocessing and splicing activities at a microRNA-containing intron.
Janas MM, Khaled M, Schubert S, Bernstein JG, Golan D, Veguilla RA, Fisher DE, Shomron N,
Levy C, Novina CD.
PLoS Genet. 2011 Oct;7(10):e1002330.
Lineage-specific transcriptional regulation of DICER by MITF in melanocytes.
Levy C, Khaled M, Robinson KC, Veguilla RA, Chen PH, Yokoyama S, Makino E, Lu J, Larue L,
Beermann F, Chin L, Bosenberg M, Song JS, Fisher DE.
Cell. 2010 Jun 11;141(6):994-1005.
Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma.
Levy C, Khaled M, Iliopoulos D, Janas MM, Schubert S, Pinner S, Chen PH, Li S, Fletcher AL,
50
Minimal engagement of CD103 on cytotoxic T lymphocytes with an E-cadherin-Fc molecule triggers
lytic granule polarization via a phospholipase Cgamma-dependent pathway.
LE FLOC’H A, JALIL A, FRANCISZKIEWICZ K, VALIDIRE P, VERGNON I and MAMI-CHOUAIB F.
Cancer Res. 2011. 71: 328-38.
c-Myc regulates NKG2D ligands ULBP1, ULBP2 and ULBP3 expression in Acute Myeloid Leukemia
and modulates their susceptibility to Natural Killer-mediated lysis.
NANBAKHSH A, POCHON C, MALAVIALLE A, AMSELLEM S, BOURHIS JH and CHOUAIB S.
Blood. 2014 Jun 5;123(23):3585-95.
Engagement of CD103 or LFA-1 at the immune synapse formed between CTL and specific tumor
cells promotes its maturation and regulates T-cell effector functions.
FRANCISZKIEWICZ K, LE FLOC’H A, BOUTET M, VERGNON I, SCHMITT A and MAMI-CHOUAIB F.
Cancer Res. 2013. 73(2):617-28.
Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during
oncogenesis.
COUVÉ S, LADROUE C, LAINE E, MAHTOUK K, GUÉGAN J, GAD S, LE JEUNE H, LE GENTIL M,
NUEL G, KIM WY, LECOMTE B, PAGÈS JC, COLLIN C, LASNE F, BENUSIGLIO PR, BRESSAC-DE
PAILLERETS B, FEUNTEUN J, LAZAR V, GIMENEZ-ROQUEPLO AP, MAZURE NM, DESSEN P,
TCHERTANOV L, MOLE DR, KAELIN W, RATCLIFFE P, RICHARD S and GARDIE B.
Cancer Res. 2014 Nov 15;74(22):6554-64.
PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated
T cell activation.
NOMAN MZ, DESANTIS G, JANJI B, HASMIM M, KARRAY S, DESSEN P, BRONTE V and CHOUAIB
S. J Exp Med. 2014 May 5;211(5):781-90.
51
EA7348 - School for Advanced Studies in Public
Health (EHESP)
Director: Laurent Chambaud
Management of Health organisations / CAPRI Program
Team leader: Etienne Minvielle
Details:
Gustave Roussy, 114, rue Edouard Vaillant,
94805 Villejuif cedex
Tel.: +33(0)1 42 11 49 89
e-mail: Etienne.MINVIELLE@gustaveroussy.fr
Team members(CAPRI PROGRAM):
- Permanent researchers: 1,5 EHESP, Montréal
- Faculty members: 1 MCF à 50% EHESP
- Technical staff: 2,5 Gustave Roussy
- PhD students: 1
- Others : 1 professeur émérite, Ecole des Mines
Keywords
Clinical pathways, Bundled
payment, Care customisation,
Oral chemotherapies, Observance,
new forms of payment
The objective of this team is to develop and assess new
forms of cancer pathways. According to the theoretical
model of chronic Care (Wagner), these researches used
different economic, managerial, and social theories.
The main study is to implement a care coordination
system composed of two portals (one for patients, one for
professionals of primary care) and two nurse navigators.
Based on this new form of coordination, its assessment
will use the quality of observance of oral chemotherapies
(RDI) as the main criteria of a randomised clinical trial (1000
patients enrolled). A second step of this research project is
going to address the issues related to bundled payment that
could be applied to such care coordination systems. Other
researches projects are focused on paying for quality, care
customisation, management and prevention of nutritional
disorders and cost-benefit of less invasive strategies in the
follow up of localised prostatic cancer.
TOP 5 PUBLICATIONS
nternet-based technologies to improve cancer care coordination: current use and attitudes
among cancer patients. Girault A, Ferrua M, Lalloué B, Sicotte C, Fourcade A, Yatim F, Hébert
G, Di Palma M, Minvielle E. Eur J Cancer. 2015 Mar;51(4):551-7.
Main barriers to effective implementation of stroke care pathways in France: a qualitative study.
Gache K, Leleu H, Nitenberg G, Woimant F, Ferrua M, Minvielle E.
BMC Health Serv Res. 2014 Feb 28;14:95.
Evaluating iatrogenic prescribing: development of an oncology-focused trigger tool.
Hébert G, Netzer F, Ferrua M, Ducreux M, Lemare F, Minvielle E.
Eur J Cancer. 2015 Feb;51(3):427-35.
Factors associated with the length of stay of patients discharged from emergency department
in France.
Capuano F, Lot AS, Sagnes-Raffy C, Ferrua M, Brun-Ney D, Leleu H, Pateron D, Debaty G,
Giroud M, Minvielle E, Riou B.
Eur J Emerg Med. 2015 Apr;22(2):92-8.
Managing customization in health care: a framework derived from the services sector
literature.Minvielle E, Waelli M, Sicotte C, Kimberly JR.
Health Policy. 2014 Aug;117(2):216-27.
53
UMR 8203 CNRS:
Vectorology and therapeutic anticancer
Research Unit director: Lluis Mir
VECTOROLOGY NUCLEIC ACIDS AND ANTICANCER DRUGS
Lluis M. Mir, Karim Benihoud
NEW ANTICANCER THERAPIES
Liliane Massade, Jacques Grill
55
New anticancer therapies
Team leader: Liliane Massade
Deputy team leader : Jacques Grill
Vectorology nucleic acids and anticancer drugs
Team leader: Lluis Mir
Deputy team leader : Karim Benihoud
Details:
Details:
Tel.: +33(0)1 42 11 51 28
e-mail: liliane.massade@gustaveroussy.fr
e-mail: Jacques.grill@gustaveroussy.fr
Tel.: +33(0)1 42 11 47 92 / 45 88
e-mail: luis.MIR@cnrs.fr
e-mail: Karim.BENIHOUD@gustaveroussy.fr
Team members:
Team members:
- Permanent researchers: 2 CNRS, 1 Gustave Roussy
- Faculty members: 1 Evry, 2 Paris-Sud
- Technical staff: 1 Paris Sud, 3 Gustave Roussy
- PhD students: 6
- Others : 5 doctors, Gustave Roussy
- Permanent researchers: 3 (CNRS)
- Faculty members: 4 (Université Paris-Sud)
- Technical staff: 5 (CNRS; INSERM)
- PhD students: 8
- Autres: 2 (Gustave Roussy)
Keywords
Junction oncogene tumours, paediatric
tumours, nanomedecine, precision medicine,
next-generation sequencing, glioma,
ependymoma, neuroblastoma, patient derived
xenografts, tumour-stroma interactions,
bioinformatics.
• Summary of the research topics:
The goal of the team consists in identifying new anticancer
therapies, particularly in the paediatric cancers and in
cancers with junction oncogenes in the adults and in the
children. The targeting of junction oncogenes is achieved
through the identification of appropriate siRNA (targeting
the unique junction sequences) and their vectorisation for
therapeutic use. New methods, using click chemistry, have
been developed to prepare siRNA-squalene nanoparticles.
The effects on the tumour cells of the reduction of the
junction oncogene products in the cell are explored to find
other strategies acting synergistically with the siRNA. The
development of new strategies in children with cancer
includes a comprehensive program from clinic to the
bench and back to the clinic to develop new therapies.
Early Drug Development Program in the Department of
Paediatric and Adolescent Oncology of Gustave Roussy.
The introduction of molecular profiling in advanced
stage cancers is discovering genetic alterations of yet
unknown function. The mission of the group is to discover
and explore these new potential therapeutic targets in
original patient-derived preclinical models. The program
“Genomics and Biology of Brain Tumours” is looking for
new biomarkers and therapeutic targets in glial neoplasms
using patients cohorts from trials and avatars derived
from fresh patient’s tumours (glioma stem cell lines
and orthotopic xenografts). In depth investigations in the
biology of gliomas use cutting-edge methods particularily
to study stroma-tumour interactions. High-throughput
technologies are favoured for the discovery part (NGS
including ChIPseq and RNAseq, ShRNA screen, large scale
drug screen). Validation are performed both in vitro and in
vivo to inform the design of new therapeutic trials.
The program « Paediatric Precision Medicine and
Experimental Therapeutics » is directly linked with the
Keywords
Electroporation, Electrochemotherapy,
DNA vaccine; Adenovirus; epitope
display; vaccine; oncolytic virus; tropism;
nanoparticles, nanomedecine
The Physical Vectorology group develops electroporationbased treatments. It also investigates the fundamentals of cell
electroporation. In the frame of the antitumor electrochemotherapy
(3000+ patients treated in the EU in 2014), we have shown that cell
death is immunogenic (Calvet et al, OncoImmunology 2014). In
non viral gene transfer, we study DNA translocation across cell
membrane (F. André, submitted) and developed new protocols for
DNA vaccination (Calvet et al, Mol. Ther. – Met. & Clin. Dev. 2014).
In the basic area, we have achieved important results for the
understanding of the interaction of electric fields with cells: we
have developed new model (the membrane impermeability model)
that reconciles electroporation and electropermeabilisation.
This is the first model that allows explaining all the observation
accumulated over years. It introduces new features (chemical
reactions occurring in the membranes exposed to the porating
electric pulses) that we have experimentally confirmed, thus fully
validating our model (submitted).
in nanoparticles, bridging the synthesis of new compounds to
nanoparticles formation and testing in vitro and in vivo.
The viral vectorology group develops its actvities on Oncolytic
adenovirus, control of Adenovirus tropism and toxicity, and
vaccination using epitope display strategy. Combining oncolytic
adenovirus (Ad) with HDACi led to reduction of colon carcinoma
compared to each treatment alone (Bressy et al in revision and
one international patent). A synergistic treatment between
oncolytic adenovirus and chemotherapies has been identified. In
collaboration with the group of S. Kochanek (Ulm), we described
new oncolytic Ad bearing an hexon mutation increasing tumor
cell targeting while reducing liver toxicity (Lucas et al. 2015).
We recently described that Ad displaying fibers from non-Ad5
serotypes were strongly uptaken by Kupffer cells leading to a
reduced hepatoxicity (Raddi et al. in revision). Our current work
also aims to decipher the molecular bases controlling the efficacy
of a vaccination strategy based on adenovirus (Ad) displaying
epitopes inserted into their capsid. In parallel, the capacity of
epitope display to elicit protective immune responses against
different pathogens is examined.
The chemical vectorology group has continued the investigation
on siRNA and “activated” old drugs (e.g. ifosfamide) formulated
• 1 patent
• x ongoing industrial partnerships
• 3 patents
TOP 5 PUBLICATIONS
Monocytic cells derived from human embryonic stem cells and fetal liver share common
differentiation pathways and homeostatic functions.
Klimchenko O, Di Stefano, A, Geoerger, B; Hamidi, S; Opolon, P, Robert, T, Routhier, M, ElBenna, J, Delezoide, AL, Boukour, S, Lescure, B, Solary, E, Vainchenker, W, Norol, F.
Blood. 2011 Mar 17;117(11):3065-75.
Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer.
Urbinati G, et al. Urbinati, G. Ali, HM, Rousseau, Q, Chapuis, H, Desmaele, D, Couvreur, P,
Massaad-Massade, L.
PLoS One, 10(5), e0125277, 2015.
Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment
of diffuse intrinsic pontine glioma.
Truffaux N, Philippe, C, Paulsson, J, Andreiuolo, F; Guerrini-Rousseau, L, Cornilleau, G, Le
Dret, L, Richon, C, Lacroix, L, Puget, S, Geoerger, B, Vassal, G, Ostman, A, Grill, J.
Neuro Oncol. 2015 Jul;17(7):953-64.
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.
Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo
PJ, Ponnuswami A, Chen S, Johung TB, Sun W, Kogiso M, Du Y, Qi L, Huang Y, Hütt-Cabezas
M, Warren KE, Le Dret L, Meltzer PS, Mao H, Quezado M, van Vuurden DG, Abraham J, Fouladi
M, Svalina MN, Wang N, Hawkins C, Nazarian J, Alonso MM, Raabe EH, Hulleman E, Spellman
PT, Li XN, Keller C, Pal R, Grill J*, Monje M*.
Nat Med. 2015 Jun;21(6):555-9. (*co-senior authors)
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.
Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS,
Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ,
Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J.
Nat Genet. 2014 May;46(5):457-61.
56
TOP 5 PUBLICATIONS
Hexon modifi ation to improve the activity of oncolytic adenovirus vectors against neoplastic and
stromal cells in pancreatic cancer.
Lucas T, Benihoud K, Vigant F, Schmidt CQ, Bachem MG, Simmet T, Kochanek S. PLoS One.
2015 Feb 18;10(2):e0117254.
Association of oncolytic adenoviruses with chemotherapies: an overview and future directions.
Bressy C, Benihoud K.
Biochem Pharmacol. 2014 Jul 15;90(2):97-106.
Optimization of a gene electrotransfer procedure for efficient intradermal immunization with an
hTERT-based DNA vaccine in mice.
C. Y. Calvet, J. Thalmensi, C. Liard, T. Bestetti, E. Pliquet, T. Huet, P. Langlade-Demoyen and L.
M. Mir.
Molecular Therapy - Methods & Clinical Development, 1, 14045 (2014) doi:10.1038/
mtm.2014.45.
Comparison of the effects of the repetition rate between microsecond and nanosecond pulses:
Electropermeabilisation-induced electro-desensitization?
A. Silve, A. Guimerà Brunet, B. Al-Sakere, A. Ivorra and L.M. Mir
Biophysical Biochemical Acta – Biomembranes, 1840, 2139-2151, 2014
Electrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine
colon cancer cells.
C. Y. Calvet, D. Famin, F. M. André and L. M. Mir
OncoImmunology 2014; 3:e28131; http://dx.doi.org/10.4161/onci.28131.
57
UMR 8126 CNRS: Signalling, nuclei and innovation
in oncology
Microenvironment, exosomes and micro-RNAs in solid tumours
Team leader: Pierre Busson
Research Unit director: Joëlle Wiels
Details:
Gustave Roussy, CNRS UMR 8126, 114, rue
Edouard Vaillant, 94805 Villejuif
Tel.: +33(0)1 42 11 45 83
e-mail: Pierre.BUSSON@gustaveroussy.fr
Microenvironment, exosomes and micro-RNAs in solid tumours
Pierre Busson
Svetlana Dokudovskaya
Team members:
- Permanent researchers: 1 CNRS
(part-time)
- PhD students: 2 PhD students, Paris-Sud
University
Fanny Jaulin
Keywords
Éric Le Cam
immune restoration,
galectin-9, nasopharyngeal
carcinomas, tumour exosomes,
circulating tumour micro-ARNs
Vasily Ogryzko
Yegor Vassetzky, Marc Lipinski
Tumorigenesis and resistance to apoptosis in B lymphoma
Joëlle Wiels
Our research themes have stemmed from our study
of interactions and cellular communications in
nasopharyngeal carcinoma associated with the EpsteinBarr virus (NPC). In recent years, our themes became more
transversal. We mainly investigate the tumour exosomes as
immunosuppressive agents and tumour microRNAs as a
source of circulating biomarkers.
We have two main goals regarding galectin-9:
1) in terms of basic research, we investigate the mechanisms
of its immunosuppressive effects;
2) in terms of translational research, we work on the
characterisation and preclinical validation of anti-galectin-9
neutralising antibodies.
These antibodies may contribute to immune restoration
not only in NPC patients but also in several chronic
diseases like chronic active hepatitis B where there is an
abundant and inappropriate production of galectin-9 by
infected hepatocytes. Our research on circulating tumour
microRNAs concern NPC and ovarian carcinomas. We are
particularly interested in their potential for early assessment
of treatment response.
We have shown that NPC tumor exosomes are present in
the bloodstream and convey several immunomodulatory
proteins, including galectin-9 and the chemokine CCL20
(Klibi et al Blood 2009; JNCI Mrizak et al. 2014).
• 2 patents
TOP 5 PUBLICATIONS
Impact of exogenous galectin-9 on human T cells: contribution of the T cell receptor complex to
antigen-independent activation but not to apoptosis induction.
Lhuillier C, Barjon C, Niki T, Gelin A, Praz F, Morales O, Souquere S, Hirashima M, Wei M, Dellis
O, Busson P. J Biol Chem 2015 290(217): 16797-16811
patients.
Gattolliat CH, Le Teuff G, Combaret V, Mussard E, Valteau-Couanet D, Busson P, Bénard J,
Douc-Rasy S.
Cancer Med. 2014 Aug;3(4):998-1009.
Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de
Launoit Y, Busson P, Moralès O, Delhem N.
J Natl Cancer Inst. 2014 Dec 12;107(1):363.
Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor
abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.
Gressette M, Vérillaud B, Jimenez-Pailhès AS, Lelièvre H, Lo KW, Ferrand FR, Gattolliat CH,
Jacquet-Bescond A, Kraus-Berthier L, Depil S, Busson P.
PLoS One. 2014 Mar 11;9(3):e91325.
miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and
contributes to its tumorigenesis.
Cheung CC, Chung GT, Lun SW, To KF, Choy KW, Lau KM, Siu SP, Guan XY, Ngan RK, Yip TT,
Busson P, Tsao SW, Lo KW.
Mol Cancer. 2014 Aug 7;13:184.
Expression of two parental imprinted miRNAs improves the risk stratification of neuroblastoma
58
59
Team leader: Svetlana Dokudovskaya
Team leader: Fanny Jaulin
Details:
Details:
Tel. office: +33(0)1 42 11 48 53
Tel. lab: +33(0)1 42 11 49 20
e-mail:
Svetlana.DOKUDOVSKAYA@gustaveroussy.fr
Tel.: +33(0)1 42 11 50 68
e-mail: Fanny.JAULIN@gustaveroussy.fr
Team members:
- Technical staff: 1 Engineer
- PhD students: 1 doctorante
Team members:
- Permanent researchers : 1, CNRS
- Non-permanent researchers : 1 post doc
- PhD students : 1
Keywords
Tumour dissemination,
colorectal carcinoma, collective
invasion, polarity, cell biology,
Cysts, organoids, tumoroids
Keywords
Metabolism, signalling,
TORC1 pathway, autophagy,
tumour suppressor
with resistance to anticancer drugs. Our goal is to study
molecular basis of action of tumour suppressor NPRL2 and
its partners from the SEA/GATOR complexes. The study is
conducted both in non-tumour and oncogenic cell lines and
in a model organism – yeast S.cerevisiae.
The highly conserved Target of Rapamycin Complex 1
(TORC1) controls eukaryotic cell growth and response to
a variety of signals, including nutrients, hormones and
stresses. The pathways that convey upstream signals to
TORC1 are frequently deregulated in various cancers. A
number of proteins that function upstream of TORC1 in the
response to different stresses are tumour suppressors.
Recently a novel upstream TORC1 regulator – the SEA/
GATOR multiprotein complex - has been identified. Cancerassociated inactivation of several SEA/GATOR members
have been found in various cancers.
The specific aims are the following:
- Role of the SEA/GATOR complex in the regulation of the
TORC1 pathway, autophagy and cancer development.
- The yeast SEA complex – study of the macromolecular
structure and the function in the cellular response to
metabolic and oxidative stresses.
- Molecular basis of the NPRL2 function in the resistance to
the anticancer drugs.
In addition, low expression of GATOR member, Nprl2,
in different types of lung carcinomas was correlated
Our research focuses on collective invasion of colorectal
carcinoma (CRC), the second leading cause of cancer
related death. We aim at identifying the signalling pathways
regulating collective invasion; the factors dictating single
cell or collective invasion mode (and whether tumour cell
can alternate between these strategies) and the respective
activities of leaders (protrusive cells at the front of the
group) and followers (cells at the back).
1) We use versatile models, such as cysts (derived from cell
lines) or organoïds/tumoroïds (generated from tumours) in
order to decipher the cellular and molecular mechanisms
underlying collective invasion.
2) As a collaborative work with clinicians, we investigate
tumour dissemination toward the peritoneal cavity
(peritoneal carcinomatosis, PC), the second metastatic
site in CRC patients. We work on fresh and fixed patients’
samples in order to understand the molecular bases of PC
and identify clinical tools to improve patients’ care.
We use molecular and cell biology approaches, combining
spinning disc confocal microscopy and 3D organotypic
cultures along two main research axes:
TOP 5 PUBLICATIONS
A novel coatomer-related SEA complex dynamically associates with the vacuole in yeast and is
implicated in the response to nitrogen starvation.
Dokudovskaya S, Rout MP.
Autophagy. 2011 Nov;7(11):1392-3.
SEA you later alli-GATOR - a dynamic regulator of the TORC1 stress response pathway.
Dokudovskaya S, Rout MP.
J Cell Sci. 2015 Jun 15;128(12):2219-2228.
Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway.
Algret R, Fernandez-Martinez J, Shi Y, Kim SJ, Pellarin R, Cimermancic P, Cochet E, Sali A,
Chait BT, Rout MP, Dokudovskaya S.
Mol Cell Proteomics. 2014 Nov;13(11):2855-70.
A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with
the vacuole in Saccharomyces cerevisiae.
Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos DP, Cristea IM, Williams R,
Salamero J, Chait BT, Sali A, Field MC, Rout MP, Dargemont C.
Mol Cell Proteomics. 2011 Jun;10(6):M110.006478.
Guidelines for the use and interpretation of assays for monitoring autophagy.
Klionsky DJ, Abdalla FC, Abeliovich H, …/... Dokudovskaya S, …/... Zuckerbraun B.
Autophagy. 2012 Apr;8(4):445-544.
60
TOP 5 PUBLICATIONS
Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells.
Jaulin F, Xue X, Rodriguez-Boulan E, Kreitzer G.
Dev Cell. 2007 Oct;13(4):511-22.
KIF17 stabilizes microtubules and contributes to epithelial morphogenesis by acting at MT plus
ends with EB1 and APC.
Jaulin F, Kreitzer G.
J Cell Biol. 2010 Aug 9;190(3):443-60.
PH-domain-dependent selective transport of p75 by kinesin-3 family motors in non-polarized
MDCK cells.
Xue X, Jaulin F, Espenel C, Kreitzer G.
J Cell Sci. 2010 May 15;123(Pt 10):1732-41.
61
Team leader: Éric Le Cam
Team leader: Vasily Ogryzko
Details:
Details:
Tel.: +33(0)1 42 11 65 25 / 6348
e-mail: Vasily.OGRYSKO@gustaveroussy.fr ;
vogryzko@]gmail.com
Tel.: +33(0)1 42 11 48 74
e-mail: Eric.LECAM@gustaveroussy.fr
Team members:
Team members:
- Permanent researcher: 3 CNRS, 1 Inserm
- PhD students: 2
- Non-permanent researchers: Postdoc ARC
- PhD students: 2
Keywords
DNA Repair Replication and
Recombination - Electron
Microscopy - Atomic Force
Microscopy.
The team develops molecular imaging to characterise
structural properties of DNA and nucleoprotein complexes
involved in genome maintenance. Our research fields
concern the different pathways of dsDNA break repair
(Homologous Recombination and Non Homologous
End Joining), the mismatch repair and the regulation of
replication.
view at the level of single molecule in chromatin contexts.
Transmission Electron Microscopy (TEM) and Atomic Force
Microscopy (AFM) are associated in a complementary way to
explore these structural and dynamic properties.
A service is also proposed to characterise single
particles (viruses, exosomes, nanoparticles...) or to study
cell ultrastructure, immuno-localisation of proteins,
nanoparticles tracking, apoptosis and autophagy.
We characterise the architectures and the functionality of
various complexes involving both DNA-protein and proteinprotein interactions. The remodelling mechanisms under the
action of molecular motors such as helicases, polymerases
and topoisomerases are studied from a kinetic point of
Keywords
Proteomics, epigenetics,
chromatin, histones, in vivo
biotinylation, protein-protein
proximity
main subject of our group. Since, with the exception of DNA
methylation, most epigenetic information is encoded in
protein states, proteomics methodology is the approach of
choice for molecular epigenetics.
An important challenge of the postgenomic era is
understanding of the mechanisms of processing and coding
of epigenetic information. Epigenetic information comes in
addition to genetic information and is carried in molecular
structures other than DNA, but cannot be deduced from the
sequence of genome alone.
Chromatin, the hierarchically organised complex of
DNA, histones and non-histone proteins, is increasingly
recognised as the principal carrier of epigenetic
information. Our previous work and the planned projects
focus on development and use of proteomics tools to
study mechanisms of processing of epigenetic information
encoded in chromatin.
The role of epigenetic factors in many pathologies, in
particular, in oncogenesis, is increasingly appreciated.
Understanding the mechanisms of processing and
transmission of epigenetic information is the goal of the
emerging discipline of molecular epigenetics, and is the
TOP 5 PUBLICATIONS
Structural characterization of filaments formed by human Xrcc4-Cernunnos/XLF
complex involved in nonhomologous DNA end-joining.
Ropars V, Drevet P, Legrand P, Baconnais S, Amram J, Faure G, Márquez JA,
Piétrement O, Guerois R, Callebaut I, Le Cam E, Revy P, de Villartay JP, Charbonnier
JB. Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12663-8.
ATP-Independent Cooperative Binding of Yeast Isw1a to Bare and Nucleosomal DNA.
De Cian, A., Praly, E., Ding, F.Y., Singh, V., Lavelle, C., Le Cam, E., Croquette, V.,
Piétrement, O., and Bensimon, D. PloS one 7. (2012).
A protein ballet around the viral genome orchestrated by HIV-1 reverse transcriptase
leads to an architectural switch: From nucleocapsid-condensed RNA to Vpr-bridged
DNA. Lyonnais, S., Gorelick, R.J., Heniche-Boukhalfa, F., Bouaziz, S., Parissi, V.,
Mouscadet, J.F., Restle, T., Gatell, J.M., Le Cam, E., and Mirambeau, G. Virus research
171, 287-303. (2013).
Rad52 sumoylation prevents the toxicity of unproductive Rad51 filaments
independently of the anti-recombinase Srs2.
Esta A, Ma E, Dupaigne P, Maloisel L, Guerois R, Le Cam E, Veaute X, Coïc E.
PLoS Genet. 2013;9(10):e1003833.
Plasma hydrogenated cationic detonation nanodiamonds efficiently deliver to human
cells in culture functional siRNA targeting the Ewing sarcoma junction oncogene.
Bertrand JR, Pioche-Durieu C, Ayala J, Petit T, Girard HA, Malvy CP, Le Cam E,
Treussart F, Arnault JC.
Biomaterials. 2015 Mar;45:93-8.
TOP 5 PUBLICATIONS
Histone variant H2A.Bbd is associated with active transcription and mRNA processing in
human cells.
Tolstorukov MY, Goldman JA, Gilbert C, Ogryzko V, Kingston RE, Park PJ.
Mol Cell. 2012 Aug 24;47(4):596-607.
Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis).
Saade E, Pirozhkova I, Aimbetov R, Lipinski M, Ogryzko V.
Aging Cell. 2015 Jun;14(3):322-33.
Quantum biology at the cellular level--elements of the research program.
Bordonaro M, Ogryzko V.
Biosystems. 2013 Apr;112(1):11-30.
PUB-MS: a mass spectrometry-based method to monitor protein-protein proximity in vivo.
Kulyyassov A, Shoaib M, Pichugin A, Kannouche P, Ramanculov E, Lipinski M, Ogryzko V.
J Proteome Res. 2011 Oct 7;10(10):4416-27
PUB-NChIP--»in vivo biotinylation» approach to study chromatin in proximity to a protein of
interest. Shoaib M, Kulyyassov A, Robin C, Winczura K, Tarlykov P, Despas E, Kannouche P,
Ramanculov E, Lipinski M, Ogryzko V.
Genome Res. 2013 Feb;23(2):331-40
62
63
Team leaders: Yegor Vassetzky, Marc Lipinski
Oncogenesis and resistance to apoptosis in B lymphoma
Team leader: Joëlle Wiels
Details:
Details:
Tel.: +33(0)1 42 11 62 83
e-mail: Yegor.VASSETZKY@gustaveroussy.fr
Tel. office: +33(0)1 42 11 47 40
e-mail: Joelle.WIELS@gustaveroussy.fr
Team members:
Team members:
- PhD students: 2
- PhD students: 4
Keywords
Nucleus, chromatin,
lymphomas, FSHD, gene
therapy
Chromosomal translocations are a major cause of
lymphomas and leukaemias. Many of these translocations
involve immunoglobulin genes (Ig). Translocations often
occur during the immunoglobulin genes rearrangements in
the germinal center after B-cell export from bone marrow.
Three important B-cell differentiation events take place
in germinal centres: affinity maturation, class switching,
and formation of plasma cells and memory B-cells; at
every stage double stranded breakpoints and their repair
occur. These double stranded breaks are repaired by nonhomologous end-joining reparation in which a special ligase
joins ends of broken DNA. The most important condition for
this type of repair is spatial proximity of DNA ends to be
joined. In some cases ligase could choose “wrong” partner
for joining, which is located in close proximity and this event
would lead to translocations. We study the role of nuclear
organisation in the generation of specific translocations
in leukaemias with an emphasis on the role of oncogenic
viruses (HIV, EBV) in this process.
Facioscapulohumeral muscular dystrophy (FSHD) is a
common form of muscular dystrophy with prevalence
of 1 in 20,000. The disease has been causally related
to deletion of tandemly-arrayed 3.3 kb repeat units
on chromosome 4q35 possibly affecting chromatin
organisationand nearby gene expression. Consistently, it
has been observed that a number of genes mapping at
4q35 are over-expressed in the FSHD affected muscle. We
study the chromatin organisation of the 4q35 locus and its
role in epigenetic regulation of genes involved in FSHD and
use CRISPR/Cas9 technique to correct the genetic defect in
the 4q35 locus of FSHD patients.
Keywords
Apoptosis, lymphoma
B antigen Gb3 / CD77,
Epstein-Barr virus (EBV),
Bcl-2 family, autophagy
we study the mechanisms involved in the inactivation of
p53 by its main interactor, MDM2, as well as the apoptotic
pathways induced by the re-activation of p53. We have
shown recently that the EBV-positive tumour cells are more
resistant to apoptosis than the EBV-negative ones and
that this resistance rely on two complementary processes
induced by EBV: overexpression of the Bcl-2 anti-apoptotic
protein and high level of autophagy.
Malignant cellular clones emerge as a result of a series
of events, among which, escape from apoptotic cell death
plays an important role. We are interested in two EpsteinBarr virus (EBV)-associated malignancies, namely Burkitt’s
lymphoma (BL) and post-transplant lymphoproliferative
disease (PTLD). In our work, we aim both at 1/ better
understand the mechanisms whereby blockades of
apoptosis could contribute to the oncogenesis of these
tumours; 2/ counteract these blockades or induce apoptosis
in these cells via alternative pathways and analyse the
corresponding molecular signals.
In this context, we analyse the apoptotic signalling pathways
induced by various ligands of a glycolipid antigen (Gb3/CD7)
which is highly expressed on BL cells. On the other hand,
Finally, using xenograft murine models, we have been able to
show the important role of Bcl-2 inhibitors in the treatment
of PTLD. Our goal is now to test the efficacy and specificity
of new inhibitors of the Bcl-2 family proteins developed by
a team of chemists headed by Fanny Roussi at the Institut
de chimie des substances naturelles (ICSN, Gif sur Yvette).
• 1 patent
TOP 5 PUBLICATIONS
Joëlle Wiels
TOP 5 PUBLICATIONS
E, Belayew A, Carnac G, Laoudj-Chenivesse D, Lipinski M, and Vassetzky, Y.S.
J. Biol. Chem., 2013, 288:34989-35002.
Dynamics of double strand breaks and chromosomal translocations.
Larovaia O.V., Rubtsov, M., Ioudinkova, E., Tsfasman, T., Razin S.V., and Vassetzky, Y.S.
Mol. Cancer, 2014, 13:249
Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of key genes
in mantle cell lymphoma.
Allinne J, Pichugin A, Iarovaia O, Klibi M, Barat A, Zlotek-Zlotkiewicz E, Markozashvili D, Petrova N,
Camara-Clayette V, Ioudinkova E, Wiels J, Razin SV, Ribrag V, Lipinski M, Vassetzky YS.
Blood, 2014, Mar 27;123(13):2044-53.
Defective Regulation of miRNAs Target Genes in Myoblasts from Facioscapulohumeral Dystrophy
Patients.
Dmitriev P, Stankevicins L, Ansseau E, Petrov A, Barat A, Dessen P, Robert T, Turki A, Lazar V, Labourier
64
Transcription factories in the context of the nuclear and genome organization.
Razin, S.V., Gavrilov, A.A., Pichugin, A., Lipinski, M., Iarovaia, O.V. and Vassetzky, Y.S. ()
Nucl. Acids. Res., 2011, 39:9085-9092
Nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity: implications for the
facioscapulohumeral dystrophy.
Petrov A., Allinne J., Pirozhkova, I., Laoudj, D., Lipinski, M., and Vassetzky, Y.S.
Genome Research, 2008, 18:39-45.
Treatment with a BH3 mimetic overcomes the resistance of latency III EBV (+) cells to p53mediated apoptosis.
A. Pujals, B. Renouf, A. Robert, S. Chelouah, E. Hollville and J. Wiels.
Cell Death Dis, 2011 Jul 28;2:e184.
Constitutive autophagy contributes to resistance to p53-mediated apoptosis in Epstein-Barr
virus-positive latency III B-cell lymphoproliferations.
A. Pujals, L. Favre, C. Pioche-Durieu, A. Robert, G. Meurice, M. Le Gentil, S. Chelouah, E. Le
Cam, L.T. Vassilev, P. Codogno, M. Lipinski and J. Wiels.
Autophagy, in press
Caspase-8-mediated cleavage of Bid and Protein Phosphatase 2A-mediated activation of Bax
are necessary for Verotoxin-1-induced apoptosis in Burkitt’s lymphoma cells.
J. Garibal, É. Hollville, B. Renouf, C. Tétaud and J. Wiels
Cell Signal. 2010 22 : 467-475
Activation of wild-type p53 by MDM2 inhibitors: a new strategy for lymphoma treatment.
A. Pujals, L. Favre, P. Gaulard and J. Wiels.
Blood Lymphat Cancer : Targets and Therapy. 2015 5 : 93-100
Pro-apoptotic meiogynin A derivatives that target Bcl-xL and Mcl-1.
S. Desrat, A. Pujals, C. Colas, J. Dardenne, C. Gény, L. Favre, V. Dumontet, B. I. Iorga, M.
Litaudon, M. Raphaël, J. Wiels and F. Roussi.
Bioorg Med Chem Lett. 2014 24 : 5086-5088,
65
UMR 1015 INSERM: Tumour immunology and
immunotherapy OF CANCER
Research Unit director: Laurence Zitvogel
Sébastien Apcher
Regulation of the effector anti-tumour function
by dendritic cells and exosomes: towards the designation
Laurence Zitvogel
66
67
Team leader: Sébastien Apcher
Regulation of the effector anti-tumour function by dendritic
cells and exosomes: towards the designation
Team leader : Laurence Zitvogel
Details:
Details:
Tel.: +33(0)1 42 11 55 59
e-mail: Sebastien.APCHER@gustaveroussy.fr
Gustave Roussy, Inserm UMR 1015 and CIC1428,
Tel.: +33(0)1 42 11 50 41
e-mail: Laurence.ZITVOGEL@gustaveroussy.fr
Team members:
Team members:
- Technical staff: 2 (1 INSERM, 1 Gustave Roussy)
- Non-permanent researchers: 1 Inserm
- PhD students: 1
- PhD students: 5
- Others: 1 secretary, 1 lab attendant, 2 M.Ds at 5% ETP
Keywords
mRNA translation, pioneer
translation products (PTPs), MHC class
I presentation, antigen processing,
tumour immune response.
We have started to answer the following question:
- Since REGγ is mainly present in the same location where
the PTPs are produced, meaning the nucleus, we have
decided to look at the role of this activator in the production
or degradation process of antigenic peptides in different
tumour cell lines.
- The fact that PTPs are derived from introns also raises
the possibility that these are presented from endogenous
mRNAs during central T cell selection in the thymus in
order to prevent immune reactions against tissue-specific
spicing products. These results also show for the first time
that there are different mRNA translation events giving rise
to peptides with specific functions. We now need to know if
PTPs are also a source for cross presentation.
It is intuitively appealing and virtually assumable that the rate
of mRNA translation directly controls antigen presentation.
However, we have been able to show that it is not the control
of full length protein synthesis that determines antigen
presentation but the synthesis of pioneer translation
products, PTPs.
This is the first time that we have an idea of what antigenic
peptides are and the fact that antigenic peptides to a large
degree are derived from PTP products produced during
the first scanning of any mRNAs and not from full length
proteins has several very interesting consequences.
1/ Deciphering the molecular and cellular bases of «
immunogenic cell death » : harnessing the immunopeptidome
of tumor cells exposed to immunogenic cell death, based
on a model system of ER stress response or autophagy
proficiency or deficiency. This work is currently performed in
collaboration with Pr Kroemer (Paris Descartes and GRCC), Pr
Rammensee (University of Tübingen), Isa Pharma. (Dr Melief)
and Dr Perreault (Canada). Project based on mass spectroscopy,
peptide synthesis, preclinical tumour models with the aim of
finding an universal vaccine.
2/ Microbiome and cancer therapeutics : studying the causeeffect relationship between intestinal dysbiosis and loss of
therapeutic responses to various immunomodulators. A
collaboration with Enterome, Maat, two biotech. Cie leading
the field of metagenomics and metatranscriptomics and FMT
will allow the broad description of patients’ dysbiosis pre-and
post- therapy with polychemotherapy in breast cancer and with
immune checkpoint blockers in others. The causative effects of
deviations from the normal microbiome repertoire on anticancer
immunity and antitumour effects will be studied by human fecal
microbial transplantation into germ free mice and ATB-treated
littermates, after clustering of patients dysbiosis. The endpoints
are to study the molecular mimicry between microbes and
tumour antigens and to clone a high avidity TCR cross reacting
between tumour cells and intestinal antigens.
3/ Harnessing novel immune checkpoints or activating receptors
in the immune system : By studying the transcriptional profiling
of TILs in GIST responders and non responders, who exhibit
the immunostimulatory versus immunosuppressive NKp30
phenotype, we found gene candidates that could be eligible to
exert ICB functions. These candidates, shared between NK and
T cells, will be probed in gene deficient mouse tumour models
to analyse their biological significance in modulating cancer
immunosurveillance.
4/ Mode of action of current immuno-oncology compounds
and predictors of responses to therapy : translational research
program projects with clinicians from bench to bedside,
performed in melanoma, lung cancer and breast tumours.
Contracts with industrial partners and biotech Cies.
• 6 patents
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer
round of mRNA translation.
Apcher S, Daskalogianni C, Lejeune F, Manoury B, Imhoos G, Heslop L, Fåhraeus R.
Proc Natl Acad Sci USA. 2011 Jul 12;108(28):11572-7.
Pioneer translation products as an alternative source for MHC-I antigenic peptides.
Apcher S, Daskalogianni C, Fåhraeus R.
Mol Immunol. 2015 May 12.
Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC
class I pathway.
Apcher S, Millot G, Daskalogianni C, Scherl A, Manoury B, Fåhraeus R.
Proc Natl Acad Sci USA. 2013 Oct 29;110(44):17951-6.
Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals
a close correlation between mRNA translation initiation and antigen presentation.
Apcher S, Daskalogianni C, Manoury B, Fåhraeus R.
PLoS Pathog. 2010 Oct 14;6(10):e1001151.
The role of mRNA translation in direct MHC class I antigen presentation.
Apcher S, Manoury B, Fåhraeus R.
Curr Opin Immunol. 2012 Feb;24(1):71-6.
68
The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide.
Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom
C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M,
Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad
N, Vivier E, Ryffel B, Elson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L.
Science. 2013 Nov 22;342(6161):971-6.
Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of
chemotherapy.
Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, Vitale I, Goubar A, Baracco EE,
Remédios C, Fend L, Hannani D, Aymeric L, Ma Y, Niso-Santano M, Kepp O, Schultze JL, Tüting
T, Belardelli F, Bracci L, La Sorsa V, Ziccheddu G, Sestili P, Urbani F, Delorenzi M, Lacroix-Triki
M, Quidville V, Conforti R, Spano JP, Pusztai L, Poirier-Colame V, Delaloge S, Penault-Llorca F,
Ladoire S, Arnould L, Cyrta J, Dessoliers MC, Eggermont A, Bianchi ME, Pittet M, Engblom C,
Pfirschke C, Préville X, Uzè G, Schreiber RD, Chow MT, Smyth MJ, Proietti E, André F, Kroemer
G, Zitvogel L.
Nat Med. 2014 Nov;20(11):1301-9.
Cancer and the gut microbiota: An unexpected link.
Zitvogel L, Galluzzi L, Viaud S, Vétizou M, Daillère R, Merad M, Kroemer G.
Sci Transl Med. 2015 Jan 21;7(271):271ps1.
Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.
Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N,
Semeraro M, Minard-Colin V, Poirier-Colame V, Chaba K, Flament C, Baud V, Authier H, KerdineRömer S, Pallardy M, Cremer I, Peaudecerf L, Rocha B, Valteau-Couanet D, Gutierrez JC, Nunès
JA, Commo F, Bonvalot S, Ibrahim N, Terrier P, Opolon P, Bottino C, Moretta A, Tavernier J, Rihet
P, Coindre JM, Blay JY, Isambert N, Emile JF, Vivier E, Lecesne A, Kroemer G, Zitvogel L.
Nat Med. 2011 Jun;17(6):700-7.
Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients
Michaela Semeraro, Sylvie Rusakiewicz, Véronique Minard-Colin, Nicolas F. Delahaye, David
Enot, Frédéric Vély, Aurélien Marabelle, Benjamin Papoular, Christelle Piperoglou, Mirco Ponzoni,
Patrizia Perri, Andrei Tchirkov, Jessica Matta, Valérie Lapierre, Tala Shekarian, Sandrine ValsesiaWittmann, Frédéric Commo, Nicole Prada, Vichnou Poirier-Colame, Brigitte Bressac, Sophie
Cotteret, Laurence Brugieres, Françoise Farace, Nathalie Chaput, Guido Kroemer, Dominique
Valteau-Couanet, Laurence Zitvogel.
Sci Transl Med Apr 2015.
69
Clinical
r e s e a rc h
70
clinical research teams
Genito-urinary cancers committee
Team leader: Laurence Albiges
Genito-Urinary cancer: Laurence Albiges
Details:
Endocrine tumours: Eric Baudin
Gustave Roussy, Medical Oncology Department,
114 rue Edouard Vaillant, 94805 Villejuif, France
Tel: +33(0)1 42 11 54 10
Email: laurence.ALBIGES@gustaveroussy.fr
Thoracic cancer: Benjamin Besse
Team members:
Oncogenetics: Olivier Caron
- Permanent Clinical Researchers:
4 medical oncologists, 2 radiation oncologists,
2 surgical oncologists, 1 radiologist, 1 pathologist, 1
biostatiscian
- Clinical research staff: 6.3 FTE clinical research assistants,
1 FTE research nurses, 1.8 FTE others
Sarcomas: Axel Le Cesne
Breast cancer: Suzette Delaloge
Brain tumour: Frédéric Dhermain
Keywords
Kidney, Prostate, Testis, Bladder,
Rare cancers, New drugs, Precision
cancer medicine, Immunotherapy,
Mechanisms of resistance
paediatric malignancies: Jacques Grill
Gastro Intestinal cancer: David Malka
Gynecologic cancer: Patricia Pautier
Haematological malignancies: Vincent Ribrag
Dermatology: Caroline Robert
Head and Neck cancer: Stéphane Temam
The team has a national and international leadership in the
field of clinical research in kidney, prostate, bladder and testis
cancers. It plays a major role in developing innovative medicines
and introducing them in standard care, such as mTOR inhibitors,
anti-angiogenic compounds, immune checkpoint inhibitors and
other targeted therapies for kidney cancer, anti-androgen therapy
(abiraterone, enzalutamide, ODM-201) for prostate cancer. The
team has established the role of intensive chemotherapy as a
curative treatment for testis cancers. An innovative translational
research program explores the resistance mechanisms to
androgen deprivation drugs (MATCH-R prostate) and intratumour
heterogeneity in prostate cancer (PETRUS), as well as the use
of tumour molecular profiling to drive optimal treatment in
metastatic renal cancer. A new project in bladder cancer was
launched to evaluate immune therapies and the role of genomic
instability in resistance to chemotherapy. Finally, the team
coordinates CARARE, the French INCa labeled network for rare
renal cancers.
• COLLABORATIONS:
- with research teams at Gustave Roussy: Inserm U981,
Inserm U1186
- Others: CARARE, GETUG, EORTC, RCCG (Renal Cross
Chanel Group
• 705 new patients
• 145 patients in trials (21 % of patients treated for a malignancy)
• 37 trials sponsored by Gustave Roussy (6), industry (15) and other academic institutions (16)
• 2 PHRC,
TOP 5 PUBLICATIONS
P21, Legouffe E22, Lagrange JL23, Linassier C24, Deplanque G25, Beuzeboc P26, Davin JL27,
Martin AL28, Habibian M28, Laplanche A2, Culine S29
Lancet Oncol. 2015 Jul;16(7):787-94.
Randomized, controlled, double-blind, cross-over trial assessing treatment preference for
pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study.
Escudier B1, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U,
Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D.
J Clin Oncol. 2014 May 10;32(14):1412-8.
Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in
asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic
castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.
Loriot Y1, Miller K2, Sternberg CN3, Fizazi K4, De Bono JS5, Chowdhury S6, Higano CS7,
Noonberg S8, Holmstrom S9, Mansbach H10, Perabo FG11, Phung D11, Ivanescu C12, Skaltsa
K13, Beer TM14, Tombal B15.
Lancet Oncol. 2015 May;16(5):509-21.
Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell
carcinoma: an open-label, randomised phase 3 trial.
Motzer RJ1, Porta C2, Vogelzang NJ3, Sternberg CN4, Szczylik C5, Zolnierek J6,
Kollmannsberger C7, Rha SY8, Bjarnason GA9, Melichar B10, De Giorgi U11, Grünwald V12,
Davis ID13, Lee JL14, Esteban E15, Urbanowitz G16, Cai C16, Squires M17, Marker M16, Shi
MM16, Escudier B18
Lancet Oncol. 2014 Mar;15(3):286-96.
Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant
prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2
dose expansion trial.
Fizazi K1, Massard C2, Bono P3, Jones R4, Kataja V5, James N6, Garcia JA7, Protheroe A8,
Tammela TL9, Elliott T10, Mattila L11, Aspegren J11, Vuorela A11, Langmuir P12, Mustonen
M11 - ARADES study group.
Lancet Oncol. 2014 Aug;15(9):975-85.
Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation
therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised
controlled trial.
Fizazi K1, Faivre L2, Lesaunier F3, Delva R4, Gravis G5, Rolland F6, Priou F7, Ferrero JM8,
Houede N9, Mourey L10, Theodore C11, Krakowski I12, Berdah JF13, Baciuchka M14, Laguerre
B15, Fléchon A16, Ravaud A17, Cojean-Zelek I18, Oudard S19, Labourey JL20, Chinet-Charrot
72
73
Endocrine tumours committee
Team leader: Eric Baudin
Thoracic cancers committee
Team leader: Benjamin Besse
Details:
Details:
Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France
Tel: +33(0)1 42 11 42 42
Email: Eric.BAUDIN @gustaveroussy.fr
Tel: +33(0)1 42 11 43 22
Email: benjamin.BESSE@gustaveroussy.fr
Team members:
Team members:
- Permanent Clinical Researchers :
5 medical oncologists,
3 radiation oncologists, 5 surgical oncologists,
6 radiologists, 4 pathologists, 1 biologist,
1 biostatiscian, 2 interventional radiology
- Clinical research staff:
3.6 FTE clinical research assistants, 0.5 FTE others
- Permanent Clinical Researchers: 5 medical oncologists,
3 pulmonologists, 2 radiation oncologists, 1 radiologists,
1 pathologist, 1 biologist, 2 biostatiscians, and Surgical oncologists
for Centre Chirurgical Marie Lannelongue
1 FTE research nurses, 1 FTE others
Keywords
Keywords
NSCLC, Mesothelioma, Thymoma, Precision cancer
medicine, Individual Molecular profiling, Targeted
therapies, Immunotherapy, early drug development,
circulating biomarkers, High Precision Radiotherapy,
SCLC, adjuvant treatments strategy
Thyroid Cancer, Adrenal gland cancer, Neuro-Endocrine
tumours, Targeted therapies, vectorised radiotherapy,
radioactive iodine therapy, European collaboration
The team is internationally recognised for clinical and
translational research on thyroid cancer, adrenal gland
cancer and neuro-endocrine tumours (NET), all being
rare cancers. The team played a major role in the recent
development of targeted agents for thyroid cancers such as
lenvatinib, vandetanib, sorafenib and cabozantinib. Through
the ambitious GR-sponsored ESTIMABL program, the
team evaluates the best strategies for radioiodine ablation
in low risk thyroid cancer in terms of toxicity and medicoeconomic elements as well as the use of robotic surgery. The
team coordinates the TUTHYREF INCA-labeled rare cancer
network to speed up innovation for patients with relapsed or
refractory thyroid cancer. The team develops and coordinates
a large European academic research program evaluating
therapeutic strategies through stratifications of prognostic
factors and first academic international randomised trials
in adrenocortical carcinoma (FIRMACT), pheochromocytoma
(FIRSTMAPP) and NETs (OCLURANDOM). The team also
coordonates the COMETE (adrenal cancer) and TENpath (NET)
INCA- labeled rare cancer networks. In collaboration with
Inserm U1185, a translational research project studies the
molecular targets and mechanism of action of mitotane, the
only drug so far with activity in adrenal cancer. The endocrine
tumour board is currently implementing a personalised
therapy program in differentiated and medullary thyroid
carcinomas, adrenal tumours and NETs in collaboration with
INSERM units.
• COLLABORATIONS:
- With research teams at Gustave Roussy : Corinne Dupuy GR
CNRS UMR8200, Sylvie Chevillard. CEA, Florent de Vathaire.
GR INSERM U1018, INSERM U1185 (Kremlin Bicetre), INSERM
U790 (Paris- HEGP) ; Massimo santoro et Sam Wells. NCI
- Others: 4 rare cancer networks – COMETE, TUTHYREF;
RENATEN, TENpath
• 657new patients
• 16 Trials (5 Gustave Roussy, 6 industry and 5 academia sponsored)
• 3 PHRC, 1 EU grant, 1 PRTK (Translational Research, INCa-Ministère de la Santé
radiotherapy, implementation of adjuvant strategies and leads
the only international trial on post-operative radiotherapy
in patients with N2 disease. Through the collaboration with
INSERM unit 981, the team explores the use of biomarkers,
such as ERCC1 and other DNA repair markers, to optimise
cisplatin- based therapy for lung cancers. The group is also
working on molecular mechanism of acquired resistance to
targeted therapies both in the lab and the clinic (MATCH-R
trial). The team coordinates RYTHMIC, the INCA- labeled
research and care network dedicated to Thymoma.
The team is exploring the implementation of precision cancer
medicine and use of both targeted agents and immune
checkpoint inhibitors (and the combination of both) through
phase I/II trials, international collaborations, in particular
in the EORTC Lung Group and the IFCT (French cooperative
intergroup)-Unicancer collaboration. The team plaid a major
role in the development of ALK, ROS1 and EGFR inhibitors. A
blood- borne biomarker test for ALK therapies was developed
with the Translational research lab. The team created the first
molecular tumour board at Gustave Roussy. Through the GR
sponsored MSN trial, a tumour molecular profiling is proposed
to all patients with a thoracic cancer since 2011. In addition,
the team leads the European screening program EORTC-ETOP
SPECTAlung and SAFIR02, a national trial of stratified medicine
based on NGS and CGH. The team has also an expertise in
early as well as locally advanced lung cancer: Phase I studies
in radiotherapy, important experience in lung stereotactic
• COLLABORATIONS:
- With research teams at Gustave Roussy: Inserm U901 981,
Inserm U1030
- Others: Chair the EORTC lung Committee, Coordinator of
the RYTHMIC INCa rare cancer network
•961 new patients
• 1 PHRC, 1 EU grant
• 1 patent
TOP 5 PUBLICATIONS
L, Bastie D, Schvartz C, Vera P, Morel O, Benisvy D, Bournaud C, Bonichon F, Dejax C, Toubert
ME, Leboulleux S, Ricard M, Benhamou E
N Engl J Med. 2012 May 3;366(18):1663-73.
Lenvatinib versus placebo in radioiodine-refractory thyroid cancer.
Schlumberger M1, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K,
Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus
CE, de las Heras B, Zhu J, Sherman SI.
N Engl J Med. 2015 Feb 12;372(7):621-30.
Combination chemotherapy in advanced adrenocortical carcinoma.
Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C,
Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux
S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la
Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H,
Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study
Group.
N Engl J Med. 2012 Jun 7;366(23):2189-97.
Tumeurs de la Thyroïde Refractaires Network for the Essai Stimulation Ablation Equivalence
Trial Strategies of radioiodine ablation in patients with low-risk thyroid cancer.
Schlumberger M1, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, Bardet S, Leenhardt
TOP 5 PUBLICATIONS
Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised,
double-blind, phase 2 trial.
Leboulleux S1, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, Gómez JM,
Bonichon F, Leenhardt L, Soufflet C, Licour M, Schlumberger MJ
Lancet Oncol. 2012 Sep;13(9):897-905.
AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.
Jänne PA1, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su
WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA,
Ghiorghiu S, Ranson M.
N Engl J Med. 2015 Apr 30;372(18):1689-99.
Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic
adrenocortical carcinoma: a double-blind, randomised, phase 3 study.
Fassnacht M1, Berruti A2, Baudin E3, Demeure MJ4, Gilbert J5, Haak H6, Kroiss M7, Quinn DI8,
Hesseltine E9, Ronchi CL10, Terzolo M11, Choueiri TK12, Poondru S13, Fleege T13, Rorig R13,
Chen J13, Stephens AW14, Worden F9, Hammer GD15.
Lancet Oncol. 2015 Apr;16(4):426-35.
ERCC1 isoform expression and DNA repair in non-small-cell lung cancer.
Friboulet L1, Olaussen KA, Pignon JP, Shepherd FA, Tsao MS, Graziano S, Kratzke R, Douillard
JY, Seymour L, Pirker R, Filipits M, André F, Solary E, Ponsonnailles F, Robin A, Stoclin A,
Dorvault N, Commo F, Adam J, Vanhecke E, Saulnier P, Thomale J, Le Chevalier T, Dunant A,
Rousseau V, Le Teuff G, Brambilla E, Soria JC.
N Engl J Med. 2013 Mar 21;368(12):1101-10.
Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M,
Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR.
N Engl J Med. 2015 Apr 30;372(18):1700-9.
Customized adjuvant phase II trial in patients with non-small-cell lung cancer: IFCT-0801
TASTE.
Wislez M1, Barlesi F, Besse B, Mazières J, Merle P, Cadranel J, Audigier-Valette C, Moro-Sibilot
D, Gautier-Felizot L, Goupil F, Renault A, Quoix E, Souquet PJ, Madroszyck A, Corre R, Pérol D,
Morin F, Zalcman G, Soria JC.
J Clin Oncol. 2014 Apr 20;32(12):1256-61.
Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive
non-small-cell lung cancer.
Pailler E1, Adam J, Barthélémy A, Oulhen M, Auger N, Valent A, Borget I, Planchard D, Taylor
M, André F, Soria JC, Vielh P, Besse B, Farace F.
J Clin Oncol. 2013 Jun 20;31(18):2273-81.
Rociletinib in EGFR-mutated non-small-cell lung cancer.
Sequist LV1, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou
V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, Garon EB,
74
75
Sarcomas Committee
Team leader: Axel Le Cesne
Oncogenetics committee
Team leader: Olivier Caron
Details:
Details:
Gustave Roussy, Genetic Clinic, Medical Oncology Department,
Tel: +33(0)1 42 11 51 78
Email: olivier.CARON@gustaveroussy.fr
Tel: +33(0)1 42 11 43 16
Email: Axel.LECESNE@gustaveroussy.fr
Team members:
Team members:
- Permanent clinical researchers: 5 medical oncologists,
4 surgical oncologists, 2 radiologists, 2 pathologists,
3 biologists, 1 biostatistician
- Clinical research staff: 0.1 FTE clinical research assistants
- Permanent Clinical Researchers: 3 Medical oncologists,
2 Radiation oncologists, 2 Surgical oncologists, 1 Radiologist,
2 Pathologists, 1 Biologists, 1 Biostatiscians (all MD)
0.7 FTE research nurses, 0.8 FTE Other
Keywords
Keywords
Genetic Predisposition, BRCA,
Mismatch Repair, TP53, APC, CDH1,
melanoma, precision cancer medicine,
screening strategy, intervention trials
The team runs its activity in care and clinical research in
close collaboration with the Breast, GI, paediatrics and
Skin committees as well as with the Genetic Laboratory
within the Biopathology Department. The team develops
follow up and screening strategies for families with genetic
predisposition to cancer (BRCA, MMR, APC, TP53, CDH1,
adults and children) and leads large national projects such as
LIFSCREEN (randomised trial evaluating surveillance of TP53
families) and TUMOSPEC (assessing the clinical utility of a
set of “new” predisposition genes). The team coordinates the
national CDH1 group and is a major contributor to national
programs such as GENEPSO (BRCA cohorts), GENESIS (breast
cancer gene discovery), OFELY (Lynch syndrome observatory),
CMMRD and some programs of gene discovery, locally mainly
on melanoma predisposition.The team is involved in the
Gustave Roussy Precision cancer Medicine programs since
whole exome sequencing of tumour and germline identifies
incidentally mutations in genes which are or potentially
are predisposing genes. In addition, intervention trials are
developed, for example using PARP inhibitors in BRCA patients
or immunotherapy in patients with high mutator phenotype.
The committee collaborates to patient selection and handles
proper genetic counselling before and after recruitment of the
subjects.
• 24 new patients
• 2 Trials (1 Gustave Roussy and 1 academia sponsored)
Soft tissue sarcomas, GIST,
fibromatosis, targeted agents, surgery,
immune therapy
type fibromatosis as well as the role of beta-catenin. The
team co-coordinates NETSARC, the INCa labeled sarcoma
network. A joint research program on bone sarcoma is being
developed with the paediatric Cancer Committee.
The team is an internationally recognised expert in the field
of care and research on soft tissue sarcomas and played a
major role in understanding GIST through the development
of targeted therapies and dynamic radiological tools.
Continuing efforts address the development of additional
innovative medicines/loco-regional approaches for this
rare cancer as well as defining the optimal therapeutic
strategy for sustained remissions. Along with Inserm
U1015, a prognostic immunogenetic biomarker has been
identified for GIST patients. Within French and international
collaborations, the team explores the role of other drugs
in sarcomas, such as trabectedine, masitinib, pazopanib
always considering introduction in standard care beyond the
need for drug approval. The team was the first to show that
observation was superior to surgical removal in desmoid-
• COLLABORATIONS:
- With (research teams at Gustave Roussy): Laurence Zitvogel
lab, Salem Chouaib team / Inserm U1015, Inserm U1186
- Others: Expert National coordinator of NETSARC network in
France. Co-Chairman of the French Sarcoma Group. Member of
the European Organisation for Research and Treatment of Cancer
Soft Tissue and Bone Sarcoma Group (STBSG), chaiman of the
systemic subcomitte of STBSG. Member of the Board of Directors of
the Connective Tissue Oncology Society. Member of the Academy of
Medicine of France
• 1 PHRC, 1 EU grant
TOP 5 PUBLICATIONS
Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers.
Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, GauthierVillars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de
Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, Frebourg T.
J Clin Oncol. 2015 Jul 20;33(21):2345-52
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.
Lavoine N, Colas C, Muleris M, Bodo S, Duval A, Entz-Werle N, Coulet F, Cabaret O, Andreiuolo
F, Charpy C, Sebille G, Wang Q, Lejeune S, Buisine MP, Leroux D, Couillault G, Leverger G,
Fricker JP, Guimbaud R, Mathieu-Dramard M, Jedraszak G, Cohen-Hagenauer O, GuerriniRousseau L, Bourdeaut F, Grill J, Caron O, Baert-Dusermont S, Tinat J, Bougeard G, Frébourg
T, Brugières L.
J Med Genet. 2015 Aug 28. pii: jmedgenet-2015-103299
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal
carcinoma.
Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, Dessen P, d’Hayer B, Mohamdi
H, Remenieras A, Maubec E, de la Fouchardière A, Molinié V, Vabres P, Dalle S, Poulalhon
N, Martin-Denavit T, Thomas L, Andry-Benzaquen P, Dupin N, Boitier F, Rossi A, Perrot JL,
Labeille B, Robert C, Escudier B, Caron O, Brugières L, Saule S, Gardie B, Gad S, Richard S,
Couturier J, Teh BT, Ghiorzo P, Pastorino L, Puig S, Badenas C, Olsson H, Ingvar C, Rouleau E,
Lidereau R, Bahadoran P, Vielh P, Corda E, Blanché H, Zelenika D, Galan P; French Familial
Melanoma Study Group, Aubin F, Bachollet B, Becuwe C, Berthet P, Bignon YJ, Bonadona
V, Bonafe JL, Bonnet-Dupeyron MN, Cambazard F, Chevrant-Breton J, Coupier I, Dalac
S, Demange L, d’Incan M, Dugast C, Faivre L, Vincent-Fétita L, Gauthier-Villars M, Gilbert
B, Grange F, Grob JJ, Humbert P, Janin N, Joly P, Kerob D, Lasset C, Leroux D, Levang J,
Limacher JM, Livideanu C, Longy M, Lortholary A, Stoppa-Lyonnet D, Mansard S, Mansuy L,
Marrou K, Matéus C, Maugard C, Meyer N, Nogues C, Souteyrand P, Venat-Bouvet L, Zattara
H, Chaudru V, Lenoir GM, Lathrop M, Davidson I, Avril MF, Demenais F, Ballotti R, Bressac-de
Paillerets B.
Nature. 2011 Oct 19;480(7375):94-8
Breast Cancer Risk Associated with Estrogen Exposure and Truncating Mutation Location in
BRCA1/2 Carriers.
Lecarpentier J, Noguès C, Mouret-Fourme E, Buecher B, Gauthier-Villars M, Stoppa-Lyonnet
D, Bonadona V, Fricker JP, Berthet P, Caron O, Coupier I, Pujol P, Faivre L, Gesta P, Eisinger
F, Mari V, Gladieff L, Lortholary A, Luporsi E, Leroux D, Venat-Bouvet L, Maugard CM, Colas C,
Tinat J, Lasset C, Andrieu N; GENEPSO.
Cancer Epidemiol Biomarkers Prev. 2015 Apr;24(4):698-707.
Hereditary diffuse gastric cancer syndrome: improved performances of the 2015 testing criteria
for the identification of probands with a CDH1 germline mutation.
Benusiglio PR, Colas C, Rouleau E, Uhrhammer N, Romero P, Remenieras A, Moretta J,
Wang Q, De Pauw A, Buecher B, Stoppa-Lyonnet D, Mouret-Fourme E, Noguès C, Di Maria M,
Tlemsani C, Warcoin M, Grandjouan S, Malka D, Caron O, Blayau M.
J Med Genet. 2015 Aug;52(8):563-5.
76
TOP 5 PUBLICATIONS
V9, Pápai Z10, Le Cesne A11, Novick S12, Taningco L12, Mo S12, Green S13, Reichardt P14,
Demetri GD15.
Lancet Oncol. 2015 May;16(5):550-60.
Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a
randomised phase 2 trial.
Le Cesne A1, Blay JY2, Domont J1, Tresch-Bruneel E3, Chevreau C4, Bertucci F5, Delcambre
C6, Saada-Bouzid E7, Piperno-Neumann S8, Bay JO5, Mir O1, Ray-Coquard I2, Ryckewaert T9,
Valentin T4, Isambert N10, Italiano A11, Clisant S12, Penel N13
Lancet Oncol. 2015 Mar;16(3):312-9.
Trabectedin in patients with advanced soft tissue sarcoma: a retrospective national analysis of
the French Sarcoma Group.
Le Cesne A1, Ray-Coquard I2, Duffaud F3, Chevreau C4, Penel N5, Bui Nguyen B6, PipernoNeumann S7, Delcambre C8, Rios M9, Chaigneau L10, Le Maignan C11, Guillemet C12,
Bertucci F13, Bompas E14, Linassier C15, Olivier T16, Kurtz JE17, Even C18, Cousin P19, Yves
Blay J20; French Sarcoma Group.
Eur J Cancer. 2015 Apr;51(6):742-50.
lternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.
Delahaye NF1, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, Paul P, Sarabi M,
Chaput N, Semeraro M, Minard-Colin V, Poirier-Colame V, Chaba K, Flament C, Baud V,
Authier H, Kerdine-Römer S, Pallardy M, Cremer I, Peaudecerf L, Rocha B, Valteau-Couanet
D, Gutierrez JC, Nunès JA, Commo F, Bonvalot S, Ibrahim N, Terrier P, Opolon P, Bottino C,
Moretta A, Tavernier J, Rihet P, Coindre JM, Blay JY, Isambert N, Emile JF, Vivier E, Lecesne A,
Kroemer G, Zitvogel L
Nat Med. 2011 Jun;17(6):700-7.
Paclitaxel Given Once Per Week With or Without Bevacizumab in Patients With Advanced
Angiosarcoma: A Randomized Phase II Trial.
Ray-Coquard IL1, Domont J1, Tresch-Bruneel E1, Bompas E1, Cassier PA1, Mir O1, PipernoNeumann S1, Italiano A1, Chevreau C1, Cupissol D1, Bertucci F1, Bay JO1, Collard O1, SaadaBouzid E1, Isambert N1, Delcambre C1, Clisant S1, Le Cesne A1, Blay JY1, Penel N2.
J Clin Oncol. 2015 Sep 1;33(25):2797-802.
Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic
gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.
Blay JY1, Shen L2, Kang YK3, Rutkowski P4, Qin S5, Nosov D6, Wan D7, Trent J8, Srimuninnimit
77
Breast cancer committee
Team leader: Suzette Delaloge
Brain Tumour Committee
Team leader: Frédéric Dhermain
Details:
Details:
Gustave Roussy, Medical Oncology Department, 114 rue Edouard
Vaillant, 94805 Villejuif, France
Tel: +33(0)1 42 11 42 93
Email: suzette.delaloge@gustaveroussy.fr
Tel: +33(0)1 42 11 62 20
Email: Frederic.DHERMAIN @gustaveroussy.fr
Team members:
- Permanent Clinical Researchers: 2 Medical Oncologist,
2 Radiation Oncologists, 4 Neurosurgeons (not at GR),
2 Neuroradiologists, 2 Neuropathologists (not at GR).
Team members:
5 medical oncologists, 4 radiation oncologists,
6 surgical oncologists, 2 radiologists,
3 pathologists, 3 biologists, 2 biostatiscians
7 FTE clinical research assistants,
Keywords
Primary brain tumours (Benign
and Malignant), Brain metastasis,
Stereotactic Radiotherapy, Functional
Imaging, Combination / Integration of
Targeted drugs and Immunotherapy.
Keywords
Breast, Molecular Medicine,
Predictive Biomarkers, Innovative
trials, personalised Prevention, Long
term toxicities, Innovative technologies
The team is a pioneer and international leader in the field of
molecular medicine for women with breast cancer and runs
a fully integrated clinical and translational research program
with UMR981 (Predictive multigenic biomarkers). The proof
of concept was made with the SAFIR01 trial showing the
feasibility of tumour molecular profiling in metastatic patients,
followed by the ongoing SAFIR02 trial matching molecular
alterations with a panel of targeted agents in the adjuvant
setting. The team leads several trials aiming at refining and
improving adjuvant treatments based on molecular profiles,
including the introduction of new anticancer agents. The
molecular medicine program is further developed in both
the preoperative setting, in order to early identify molecular
alterations to drive therapeutic decision, as well as the highrisk personalised prevention program being launched within
the Gustave Roussy strategic plan. Innovative technologies are
developed through robotic surgery for breast re-construction,
algorithms for more precised and better targeted radiation
therapy and innovative imaging for breast cancer screening.
The team leads a large national project, CANTO, exploring long
term toxicities in women with low risk breast cancer. The team
is a national leader in the field of breast cancer clinical and
translational research (UNiCANCER) and plays a key role in the
Breast international group (BIG).
• COLLABORATIONS:
- With (research teams at Gustave Roussy) : INSERM U981,
INSERM U1015
- External collaborations: EORTC, BIG, IBCSG, Solti, Jules
Bordet, Royal Marsden, DKFZ, NKI, Karolinska, Institut
Curie, many industrial partners
- Other: Dr Delaloge chairs the national Breast Cancer
Intergroup, Pr André chairs the national Personalized
Medicine group (Unicancer) and the Immune task Force
(BIG), Dr Rivera chairs the STAR group at EORTC (radiation
oncology group)
• 1 999 new patients
• 4 National grants (Inca), 3 EU grants, 4 grants from national charities,
1 long-term american grant (Breast Cancer research Fondation)
The team works in strong collaboration with neurosurgical
departments, mainly Saint Anne Hospital and Kremlin Bicêtre
University Hospital, where patients are operated on. The team
explores the use of functional imaging in improving high precision
radiation therapy of primary and secondary brain tumours,
contributes actively to EORTC clinical trials in brain tumours.
The team collaborates actively with the paediatric Cancers team
with regard to the development of precision radiation therapy,
as well as with the DITEP. Our goal is to significantly speed up
the development of innovative therapeutics for adult patients
with brain tumours (from the youngest to the oldest) through an
increased participation in early phase trials and the development
of a systematic tumour molecular profiling in collaboration
with neuropathologists and biologists. Our vision is to combine
and integrate all scientific innovations, for the direct interest of
patients.
• COLLABORATIONS:
- With research teams at Gustave Roussy: DITEP, paediatric
team
- Others: Member of the POLA, a INCa – labeled rare cancer
network in brain tumours (ANOCEF)
• 4 Trials (1 industry and 3 academia sponsored)
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Zhang Y, Ali S, Taran T, Gianni L.
Lancet Oncol. 2014 May;15(6):580-91
Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients
with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind,
multicentre trial.
Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu
D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran
T, Slamon D.
Lancet Oncol. 2015 Jul;16(7):816-29.
Comparative genomic hybridisation array and DNA sequencing to direct treatment of
metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER).
André F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, Lacroix-Triki M, Lacroix
L, Cohen P, Gentien D, Adélaide J, Dalenc F, Goncalves A, Levy C, Ferrero JM, Bonneterre J,
Lefeuvre C, Jimenez M, Filleron T, Bonnefoi H.
Lancet Oncol. 2014 Mar;15(3):267-74.
Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.
Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang
K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M.
N Engl J Med. 2015 Jul 16;373(3):209-19
Cost effectiveness of molecular profiling for adjuvant decision making in patients with nodenegative breast cancer.
Bonastre J, Marguet S, Lueza B, Michiels S, Delaloge S, Saghatchian M.
J Clin Oncol. 2014 Nov 1;32(31):3513-9.
Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer
(BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial.
André F, O’Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F,
Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D,
78
Systematic review and meta-analysis of phase I/II targeted therapy combined with radiotherapy
in patients with glioblastoma multiforme: quality of report, toxicity, and survival.
dos Santos MA1, Pignon JP, Blanchard P, Lefeuvre D, Levy A, Touat M, Louvel G, Dhermain F,
Soria JC, Deutsch E, Le Teuff G.
J Neurooncol. 2015 Jun;123(2):307-14.
Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse
low-grade gliomas.
Pallud J1, Llitjos JF, Dhermain F, Varlet P, Dezamis E, Devaux B, Souillard-Scémama R, Sanai
N, Koziak M, Page P, Schlienger M, Daumas-Duport C, Meder JF, Oppenheim C, Roux FX
Neuro Oncol. 2012 Apr;14(4):496-505.
ANOCEF guidelines for the management of brain metastases.
Le Rhun É, Dhermain F, Noël G, Reyns N, Carpentier A, Mandonnet E, Taillibert S, Metellus P –
ANOCEF:Association des neuro-oncologues d’expression française.
Cancer Radiother. 2015 Feb;19(1):66-71.
Advanced MRI and PET imaging for assessment of treatment response in patients with
gliomas.
Dhermain FG, Hau P, Lanfermann H, Jacobs AH, van den Bent MJ.
Lancet Neurol. 2010 Sep;9(9):906-20.
Pseudoprogression after high-dose busulfan-thiotepa with autologous stem cell
transplantation and radiation therapy in children with brain tumors: Impact on survival.
Negretti L1, Blanchard P, Couanet D, Kieffer V, Goma G, Habrand JL, Dhermain F, ValteauCouanet D, Grill J, Dufour C.
Neuro Oncol. 2012 Nov;14(11):1413-21.
79
paediatric Malignancies committee
Team leader: Jacques Grill
Gastrointestinal cancers committee
Team leader: David Malka
Details:
Details:
Tel: +33(0)1 42 11 62 09
Email: Jacques.GRILL@gustaveroussy.fr
Tel: +33(0)1 42 11 50 42
Email: david.MALKA@gustaveroussy.fr
Team members:
Team members:
- Permanent Clinical Researchers: 8medical oncologists,
2 radiation oncologists, 5 surgical oncologists (not at GR),
2 radiologists (1 not at GR), 2 pathologists (not at GR)
1 biologist, 3 biostatiscians
2 gastrointestinal endoscopists, 3 radiation oncologists,
4 surgical oncologists, 2 radiologists, 3 interventional radiologists,
1 pathologist, 1 biologist, 1 biostatistician
- Clinical research staff: 2,5 FTE clinical research assistants,
0,3 FTE research nurses, 0,7 FTE others
Keywords
Keywords
Neuroblastoma, Brain tumours, Sarcomas,
Lymphomas, Hepatoblastoma, New drugs, Precision
cancer medicine, Immunotherapy, Survivorship,
Oncogenetics, Adolescents and Young adults
for innovative therapies for children with cancer (ITCC). The
Adolescents and Young Adults care and clinical research program
is developed with the Medical Oncology Department. Strong
collaborations are ongoing with UMR 8203 on brain tumours
genomics, new preclinical models and experimental therapies,
UMR 1015 on immunology of paediatric malignancies and UMR
1018/CESP on long term toxicity including genetic predisposition
and new statistical designs for trials in rare and ultra-rare
populations.
The team is internationally recognised for its expertise and
its clinical and translational research program in paediatric
malignant solid tumours (neuroblastoma, bone and soft tissue
sarcomas, lymphoma, hepatoblastoma) and brain tumours. The
team plays a major role in leading European randomised trials in
these rare and very rare malignancies. Three innovative programs
are run: Precision cancer medicine and the development of new
oncology drugs, including immunotherapies (European leader
in paediatric early phase trials ), Exploring long –term toxicity in
childhood cancer survivors, Predisposition to pediatric cancers
through a large implementation of whole genome sequencing.
The team co-pilots with the DITEP the INCa labelled Early phase
Center (CLIPP) and plays a leading role in the European network
• COLLABORATIONS:
- With research teams at Gustave Roussy: CNRS UMR 8203,
Inserm U1015, Inserm U1018
- Others: CLIPP, canpedif
• 4 PHRC, 3 EU grants
Colorectal cancer, liver,
biliary tract, peritoneum,
locoregional therapy,
immunotherapy, new drugs
new project combining them with immunotherapy was just
launched recently. The molecular and cellular mechanisms
of dissemination and metastases are being unraveled in
collaboration with F Jaulin (CNRS UMR 8126). The team is a
major contributor to the EORTC GI group and plays a major
role in care and research on rare GI cancers within the INCalabeled networks.
The team takes care of patients having a cancer in any of the
10 GI organs and runs a clinical and translational research
program in 7 of them: colorectal, liver, biliary, stomach,
pancreatic and peritoneal cancers as well as intestinal
neuroendocrine tumours jointly with the Endocrine tumour
committee. The program explores new anticancer drugs in
collaboration with the DITEP, with a special focus on rare
tumours (the GR BINGO trial in biliary cancer). There is a large
program evaluating innovative locoregional therapies (hepatic
intra-arterial chemotherapy, hyperthermic intra peritoneal
chemotherapy, stereotactic radiation therapy, intra-tumoural
treatments, endoscopy and interventional radiology) and a
• COLLABORATIONS:
- With research teams at Gustave Roussy: F Jaulin (UMR
8126)
- Other: RENAPE, RENATEN
• 3 PHRC
TOP 5 PUBLICATIONS
SL, Raphael M, Lamant L, Klapper W, Mussolin L, Poirel HA, Macintyre E, Damm-Welk C,
Rosolen A, Patte C.
J Clin Oncol. 2015 Aug 24.
Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.
Taylor KR1, Mackay A1, Truffaux N2, Butterfield YS3, Morozova O4, Philippe C2, Castel D2,
Grasso CS5, Vinci M6, Carvalho D6, Carcaboso AM7, de Torres C7, Cruz O7, Mora J7, EntzWerle N8, Ingram WJ9, Monje M10, Hargrave D11, Bullock AN12, Puget S13, Yip S3, Jones C6,
Grill J2.
Nat Genet. 2014 May;46(5):457-61.
Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk
Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial.
Le Deley MC1, Paulussen M2, Lewis I2, Brennan B2, Ranft A2, Whelan J2, Le Teuff G2, Michon
J2, Ladenstein R2, Marec-Bérard P2, van den Berg H2, Hjorth L2, Wheatley K2, Judson I2,
Juergens H2, Craft A2, Oberlin O2, Dirksen U2
J Clin Oncol. 2014 Aug 10;32(23):2440-8.
Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.
Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo
PJ, Ponnuswami A, Chen S, Johung TB, Sun W, Kogiso M, Du Y, Qi L, Huang Y, Hütt-Cabezas
M, Warren KE, Le Dret L, Meltzer PS, Mao H, Quezado M, van Vuurden DG, Abraham J, Fouladi
M, Svalina MN, Wang N, Hawkins C, Nazarian J, Alonso MM, Raabe EH, Hulleman E, Spellman
PT, Li XN, Keller C, Pal R, Grill J, Monje M.
Nat Med. 2015 Jun;21(6):555-9. (Grill co-senior author).
Time to diagnosis of Ewing tumors in children and adolescents is not associated with
metastasis or survival: a prospective multicenter study of 436 patients.
Brasme JF1, Chalumeau M2, Oberlin O2, Valteau-Couanet D2, Gaspar N2.
J Clin Oncol. 2014 Jun 20;32(18):1935-40.
Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective
Collaboration, Current Knowledge, and Challenges Ahead.
Minard-Colin V, Brugi√®res L, Reiter A, Cairo MS, Gross TG, Woessmann W, Burkhardt B,
Sandlund JT, Williams D, Pillon M, Horibe K, Auperin A, Le Deley MC, Zimmerman M, Perkins
TOP 5 PUBLICATIONS
R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou JF, Benchimol D, Berger A, Lagarde A,
Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V.
PLoS Med 2013;10(5):e1001453.
Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer
(FFCD 2000-05): an open-label, randomised, phase 3 trial.
Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M,
Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B,
Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD)
2000–05 Collaborative Group.
Lancet Oncol 2011;12:1032-44.
Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer
(BINGO): a randomised, open-label, non-comparative phase 2 trial.
Malka D, Cervera P, Foulon S, Trarbach T, de la Fouchardière C, Boucher E, Fartoux L, Faivre
S, Blanc JF, Viret F, Assenat E, Seufferlein T, Herrmann T, Grenier J, Hammel P, Dollinger M,
André T, Hahn P, Heinemann V, Rousseau V, Ducreux M, Pignon JP, Wendum D, Rosmorduc O,
Greten TF; BINGO investigators.
Lancet Oncol 2014;15:819-28.
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL,
Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, PéréVergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe
Tumeurs Digestives of Unicancer; PRODIGE Intergroup.
N Engl J Med 2011;364:1817-25.
Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566
patients with 1037 metastases.
de Baère T, Aupérin A, Deschamps F, Chevallier P, Gaubert Y, Boige V, Fonck M, Escudier B,
Palussiére J.
Ann Oncol 2015;26:987-91.
Gene expression classification of colon cancer into molecular subtypes: characterization,
validation, and prognostic value.
Marisa L, de Reyniès A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa
80
81
Gynecologic cancers committee
Team leader: Patricia Pautier
haematological malignancies committee
Team leader: Vincent Ribrag
Details:
Tel: +33(0)1 42 11 43 40
Email: patricia.PAUTIER@gustaveroussy.fr
Details:
Gustave Roussy Medical Oncology Department,
114 rue Edouard Vaillant, 94805 Villejuif France
Tel: + 33(0)1 42 11 45 07
Email: vincent.RIBRAG@gustaverousssy.fr
Team members:
2 medical oncologists, 1 medical oncologist/clinical scientist,
3 radiation oncologists, 3 surgical oncologists, 1 radiologist,
1 pathologist, 1 biostatiscian,
2.8 FTE clinical research assistants,
0.8 FTE research nurse, 0.7 FTE other
Team members:
6 medical hematologists, 0.5 radiation oncologists,
1 pathologists, 3 biologists, 0.5 biostatiscians,
Keywords
ovarian, endometrial and
cervical cancers, DNA repair and
resistance to DNA managing
agents, Molecular profiling
The clinical research program addresses the development
of innovative treatments in ovarian, endometrial and cervical
cancers, including very rare entities such as leiomyosarcomas
(role of trabectedin) through a multidisciplinary approach. Team
members co-coordinate the INCa labeled networks on rare
gynaecological malignancies and cancer during pregnancy.
In addition, a team member leads an innovative translational
research program exploring DNA repair in resistance to cisplatinand PARP inhibitors-based therapies taking advantage of access
to sequential tumour samples. The team has already introduced
biomarkers in routine diagnosis such as B-RAF in Borderline
tumours, K-RAS and HER2 in mucinous cancer and FoxL2 in
granulosa tumours, as well as JAZF1 and YWHA1 translocations
in endometrial sarcomas. Recently, they unraveled the role of
SMARCA4 in small cell ovarian carcinoma, a very rare entity.
Prospective studies in radiation oncology aim at therapeutic
optimisation in cervical cancer through image-guided adaptive
brachytherapy, as well as innovative chemoradiation in cervical
cancer using HPV targeting drugs. Prospective studies in surgery
aim at therapeutic optimisation in ovarian cancer through an
histology-driven treatment algorithm including sequential
tumor sampling to characterise the chemo-resistant ovarian
cancer cells (PHRC 2015), and to evaluate the role of tumour
microenvironment in the primary tumour and the synchronous
metastatic lesions (EOC-IO project). In addition, the robotic
surgery offers new strategies in cervical and endometrial cancer.
• COLLABORATIONS:
- With research teams at Gustave Roussy: Philippo Roselli Inserm
8200 CNRS UMR 8200, labo immuno L Zitvogel et A Marabelle
Inserm U1015, Anapath TR team : Julien Adam Histopathology
- Academic: Memorial Sloan Kettering (Prof Abi-Rustum), Cornell
(Prof Rubin)
- Industry: Pharmamar, Inivata, Fondation medecine
- Others: (National reference center (among 3) for ovarian rare
tumors (www.ovaire-rare.org.); TransPORTEC International
RT Consortium, Coordinateur francais; ENGOT (European
Network of Gyn Onc Trial Groups) Translational Research Group
: Coordinateur francais; GINEGEPS (GINECO Group for Early
Phase Studies): Coordinateur pour les études translationnelles
associées aux essais cliniques du GINECO
• Academic grants: 1 PAIR INCA, 1 revolution cancer, Oakland Medical research foundation (20,000) ; Cancéropole
TOP 5 PUBLICATIONS
Lhommé C, Leary A, Uzan C, Pautier P, Gouy S, Morice P
J Clin Oncol. 2014 1;32(25):2815-6
Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or softtissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial.
Pautier P1, Floquet A2, Chevreau C3, Penel N4, Guillemet C5, Delcambre C6, Cupissol D7, Selle
F8, Isambert N9, Piperno-Neumann S10, Thyss A11, Bertucci F12, Bompas E13, Alexandre J14,
Collard O15, Lavau-Denes S16, Soulié P17, Toulmonde M2, Le Cesne A18, Lacas B19, Duffaud
F20; French Sarcoma Group. Lancet Oncol. 2015; 16(4):457-64.
Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast
Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).
Leary A, Evans A, Johnston SR, A’Hern R, Bliss JM, Sahoo R, Detre S, Haynes BP, Hills M,
Harper-Wynne C, Bundred N, Coombes G, Smith I, Dowsett M.
Clin Cancer Res. 2015 1;21(13):2932-40.
Prospective multicenter study evaluating the survival of patients with locally advanced cervical
cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in
the era of positron emission tomography imaging.
Gouy S, Morice P, Narducci F, Uzan C, Martinez A, Rey A, Bentivegna E, Pautier P, Deandreis D,
Querleu D, Haie-Meder C, Leblanc E. J Clin Oncol. 2013 20; 31(24):3026-33.
Impact of treatment time and dose escalation on local control in locally advanced cervical
cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.
Mazeron R, Castelnau-Marchand P, Dumas I, del Campo ER, Kom LK, Martinetti F, Farha G,
Tailleur A, Morice P, Chargari C, Lefkopoulos D, Haie-Meder C.
Radiother Oncol. 2015 Feb;114(2):257-6
Adjuvant chemotherapy in stage I ovarian germ cell tumors: should indications and treatment
modalities be different in young girls and adults?
82
Keywords
lymphomas, de novo and therapyrelated AML, CMML, MPN, innovative
drugs, precision cancer medicine,
integrated translational research
Next generation sequencing is routinely set up to prospectively
drive treatment decisions for patients with lymphomas. The
team plays a major role in the French LYSA group and in
CALYM, the recently launched National Institut Carnot project.
The team runs a clinical and translational research program
in lymphoid and myeloid malignancies in close collaboration
with UMR1170. The team is an international leader in the
field of innovative compounds and early drug trials through
a strong collaboration with the DITEP, as illustrated by
the development of JAK2 inhibitors in myeloproliferative
neoplasms, epigenetic drugs (IDH and EZH2 inhibitors), as
well as immune checkpoints inhibitors (CD70, PD1, CD-137).
The development of innovative compounds is fully integrated
into a basic and translational research programs exploring
the molecular mechanisms of haematological malignancies,
with a special focus on MPN and myelodysplastic syndrome.
• COLLABORATIONS:
- With research teams at Gustave Roussy: Inserm UMR
1170, CNRS UMR 8126
- Other: European Mantle cell lymphoma network leader
EDD (V. Ribrag)
TOP 5 PUBLICATIONS
Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid
leukemia: a study by the Acute Leukemia French Association group.
Janin M, Mylonas E, Saada V, Micol JB, Renneville A, Quivoron C, Koscielny S, Scourzic L,
Forget S, Pautas C, Caillot D, Preudhomme C, Dombret H, Berthon C, Barouki R, Rabier D,
Auger N, Griscelli F, Chachaty E, Leclercq E, Courtier MH, Bennaceur-Griscelli A, Solary E,
Bernard OA, Penard-Lacronique V, Ottolenghi C, de Botton S.
J Clin Oncol. 2014 Feb 1;32(4):297-305
An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients
with Relapsed or Refractory Hodgkin Lymphoma.
von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S, Aquino R,
Kotoulek S, de Boer CJ, Engert A.
Clin Cancer Res. 2015 Apr 15;21(8):1843-50
A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with
myelofibrosis.
Verstovsek S, Hoffman R, Mascarenhas J, Soria JC, Bahleda R, McCoon P, Tang W, CortesJ,
Kantarjian H, Ribrag V.
Leuk Res. 2015 Feb;39(2):157-63.
Perinucleolar relocalization and nucleolin as crucial events in the transcriptional activation of
key genes in mantle cell lymphoma.
Allinne J, Pichugin A, Iarovaia O, Klibi M, Barat A, Zlotek-Zlotkiewicz E, Markozashvili D, Petrova
N, Camara-Clayette V, Ioudinkova E, Wiels J, Razin SV, Ribrag V, Lipinski M, Vassetzky YS.
Blood. 2014 Mar 27;123(13):2044-53.
A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate,
administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell
non-Hodgkin lymphoma.
Ribrag V, Dupuis J, Tilly H, Morschhauser F, Laine F, Houot R, Haioun C, Copie C, Varga A,
Lambert J, Hatteville L, Ziti-Ljajic S, Caron A, Payrard S, Coiffier B.
Clin Cancer Res. 2014 Jan 1;20(1):213-20
83
Dermatology committee
Team leader: Caroline Robert
Head and Neck cancers committee
Team leader: Stéphane Temam
Details:
Details:
Gustave Roussy, Dpt of Head&Neck Surgical Oncology, 114 rue Edouard
Tel: +33(0)1 42 1144 46
Email: stephane.TEMAM@gustaveroussy.fr
Tel: +33(0)142 11 42 53
Email: Caroline.ROBERT@gustaveroussy.fr
Team members:
Team members:
1,5 radiation oncologists, 4 surgical oncologists,
1 radiologist, 1,5 pathologists, 1,25 biostatiscians
3,8 FTE clinical research assistants, 0,2 FTE others
- Permanent Clinical Researchers :
3 dermato-oncologists, 1 radiation oncologists,
3 surgical oncologists, 1 radiologist, 1 pathologists,
1 biologist, 1 biostatiscian, 4.2 FTE clinical research assistants,
0,4 FTE research nurses, 2 FTE others
4.2 FTE clinical research assistants,
0,4 FTE research nurses, 2 FTE others
Keywords
Head and neck cancer, antiEGFR inhibitors, immunotherapy,
microsatellite biomarkers,
translational research, targeted
therapies, human papilloma virus
Keywords
Melanoma, Skin toxicity,
targeted therapies, Immune
checkpoint inhibitors,
Biomarkers, Genetics
The team is an international leader in the field of innovative
medicines for melanoma patients (as illustrated by 13
publications in NEJM) and plaid a major role in the development
of B-RAF and MEK targeted agents, and anti-CTLA4 and
anti-PD1 check point inhibitors. In collaboration with Inserm
U981 the team is exploring the mechanisms of resistance of
melanoma to targeted as well as immunologic therapies. The
team will develop further the combined therapies that will
continue to transform the prognosis of melanoma patients
using algorithm of biomarkers to drive therapy. Since 2011,
the GR sponsored MSN trial develops molecular profiling. In
addition, the team runs a research program on skin toxicity
induced by innovative therapies such as EGFR inhibitors.
Patients are proposed to participate to the GR sponsored
SKIN target project which collects skin biopsies and photos to
understand the mechanisms of skin toxicity.
• COLLABORATIONS:
- With research teams at Gustave Roussy: Inserm U981
- Other: Chair of the Melanoma Group EORTC
• 1 PHRC
screening as well as adjusted treatments (to decrease long term
toxicity) using fast track IMRT, robotic surgery and de-escalated
intensity of chemotherapy. The team coordinates the French
INCa-labeled REFCOR network on rare head and neck cancers.
The team develops radiochemotherapy of head and neck cancers
combining with highly expert surgery (to preserve organ functions),
introducing innovative targeted agents such as new anti-EGFR
inhibitors and more recently immunotherapies. ELAN is an,
ongoing large national comprehensive program evaluating new
standard treatments of head neck cancers in the elderly according
to their physiological status ( a joint Gustave Roussy and GORTEC
project). A large translational research program explores the
use of microsatellite biomarkers to define the optimal margins
for surgical removal and molecular tumour profiling for targeted
therapies. A new program on Human Papiloma Virus positive head
and neck tumours was launched including prevention and early
• COLLABORATIONS:
- With research teams at Gustave Roussy: UMR 8126 CNRS
(P Busson), Imaging and cytometry platform (C Laplace),
Inserm U1138 (G Kroemer), Inserm U1015 (N Chaput)
Inserm U981 (F André) Inserm U1030 (E Deutsch)
- Other: REFCOR, GETTEC, GORTEC, INTERGROUPE ORL,
Unicancer ORL
• 2 PHRC, 2 EU grants
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos
J, Rubin SD, Little SM, Schadendorf D.
N Engl J Med. 2015 Jan 1;372(1):30-9.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C,
Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R,
Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators.
N Engl J Med. 2015 Jun 25;372(26):2521-32.
eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies.
Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, Thomas
T, Basmadjian C, Ribeiro N, Thuaud F, Mateus C, Routier E, Kamsu-Kom N, Agoussi S,
Eggermont AM, Désaubry L, Vagner S* and Robert C*. (* Co-last author)
Nature. 2014 Sep 4;513(7516):105-9.
Nivolumab in previously untreated melanoma without BRAF mutation.
Robert C1, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil
C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbé C, Charles J, Mihalcioiu C, ChiarionSileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, LundgrenEriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA.
N Engl J Med. 2015 Jan 22;372(4):320-30.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
Robert C1, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori
A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M,
Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD.
N Engl J Med. 2011 Jun 30;364(26):2517-26
Improved overall survival in melanoma with combined dabrafenib and trametinib.
Robert C1, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser
M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A,
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Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without
concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an
open-label phase 3 randomised trial.
Bourhis J1, Sire C, Graff P, Grégoire V, Maingon P, Calais G, Gery B, Martin L, Alfonsi M,
Desprez P, Pignon T, Bardet E, Rives M, Geoffrois L, Daly-Schveitzer N, Sen S, Tuchais C,
Dupuis O, Guerif S, Lapeyre M, Favrel V, Hamoir M, Lusinchi A, Temam S, Pinna A, Tao YG,
Blanchard P, Aupérin A.
Lancet Oncol. 2012 Feb;13(2):145-53.
MAC-NPC Collaborative Group Chemotherapy and radiotherapy in nasopharyngeal carcinoma:
an update of the MAC-NPC meta-analysis.
Blanchard P1, Lee A2, Marguet S3, Leclercq J3, Ng WT2, Ma J4, Chan AT5, Huang PY4,
Benhamou E1, Zhu G6, Chua DT7, Chen Y4, Mai HQ8, Kwong DL9, Cheah SL10, Moon J11, Tung
Y12, Chi KH13, Fountzilas G14, Zhang L8, Hui EP5, Lu TX8, Bourhis J15, Pignon JP16
Lancet Oncol. 2015 Jun;16(6):645-55.
LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients
with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or
after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler
T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del
Campo JM, Cong XJ, Ehrnrooth E, Cohen EE
Lancet Oncol. 2015 May;16(5):583-94.
MET genetic abnormalities unreliable for patient selection for therapeutic intervention in
oropharyngeal squamous cell carcinoma.
Lacroix L1, Post SF2, Valent A1, Melkane AE3, Vielh P1, Egile C4, Castell C4, Larois C5, Micallef
S6, Saulnier P7, Goulaouic H4, Lefebvre AM5, Temam S3
PLoS One. 2014 Jan 17;9(1):e84319.
Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de
Launoit Y, Busson P, Moralès O, Delhem N.
J Natl Cancer Inst. 2014 Dec 12;107(1):363
85
Psycho-oncology Unit
Director: Sarah Dauchy
Details:
Gustave Roussy, Supportive care Department, 114 rue Edouard
Tel: +33(0)1 42 11 46 30
Email: sarah.dauchy@gustaveroussy.fr
Team members:
- Permanent Clinical Researchers: 8 clinical psychologists (PhD)
and 2 psychiatrists
- Clinical research staff: 0,6 FTE specifically dedicated to research
- Faculty members: 1 Associate Professor (MCU), 5 part-time
teachers at University
Research in psycho-oncology is characterized by the
consideration of psychological factors in the interaction
with the patient environment (for example, the study of
communication between the physician and the patient,
researches on the psychological and emotional impact
of social support, or on the psychological determining
factors of quality of life). Psycho-oncology also studies the
interconnection between psychopathological factors in the
experience of illness, and the help and support processes.
Matching psycho-oncology researches with clinical practice
is the guarantee of the operationalization of the results and
of an efficient translational research.
• COLLABORATIONS:
- With research teams at Gustave Roussy: Dermatology
Unit, Breast Cancer Unit, Head and Neck Unit, Pediatric
department, Oncogenetics Department
- Other: UNICANCER, Paris-Sud University (EA1610), Paris
Descartes University (LPPS, EA4057), Bourgogne University
(LPPM, EA 4452), INSERM (U 1153)
3576 patients in the clinical active file
150 patients in trials (CANTO-COG, CANTO-REDUC, LIFSCREEN)
CANTO Cohort – Quality of Life and psychological evaluation (Coordinator: Sarah Dauchy)
TOP 5 PUBLICATIONS
Impact of skin toxicities associated with targeted cancer therapies on body Image: a prospective
study. Charles, C., Razavi, D., Bungener, C., Mateus, C., Lanoy, E., Verschoore, M., Robert, C.
Clinical drug investigation 2016, 1-8.
Relations between arthralgia and fear of recurrence: results of a cross-sectional study of breast
cancer patients treated with adjuvant aromatase inhibitors therapy. Lopez, C., Charles, C.,
Rouby, P., Boinon, D., Laurent, S., Rey, A., Dauchy, S. Supportive Care in Cancer 2015, 1-8.
Antidepressants for the treatment of depression in people with cancer. Ostuzzi, G., Matcham, F.,
Dauchy, S., Barbui, C., & Hotopf, M. (2015). Cochrane Database Syst Rev, 6.
Changes in psychological adjustment over the course of treatment for breast cancer: The
predictive role of social sharing and social support. Psycho-Oncology. Boinon, D., Sultan, S.,
Charles, C., Stulz, A., Guillemeau, C., Delaloge, S., Dauchy, S. 2014 ; 23, 291-298.
Describing and understanding depression in spouses of cancer patients in palliative phase.
Fasse, L., Flahault, C., Brédart, A., Dolbeault, S., Sultan, S. Psycho‐Oncology, 2015 24(9):1131-7
86
Clinical Research DIVISION
Director : Gilles Vassal
BIOSTATISTICS AND EPIDEMIOLOGY UNIT(SBE): Ellen Benhamou
Clinical Research Operations Unit (SORC): Valérie Dejean
Pharmacovigilance Unit (UFPV): Salim Laghouati
Trial Sponsoring Unit: Delphine Vuillier-Legoff
89
Biostatistic and epidemiology Unit
Head: Ellen Benhamou
Clinical Research Operations Unit
Head: Valérie Dejean
Details:
Details:
Gustave Roussy, 114 r Edouard Vaillant 94805 Villejuif, France
Tel: +33(0)1 42 11 41 44 – Fax: +33(0)1 42 11 52 58
Email: ellen.benhamou@gustaveroussy.fr
Tel: +33(0)1 42 11 56 20
Email: valerie.DEJEAN @gustaveroussy.fr
Team members:
Team members:
4 Clinical Research Assistant Managers, 58 CRA, 1 Medical
Research Assistant Referent,
3 MRA, 1 Study Nurse Coordinator, 7 SN, 3 Research Technicians,
2 Project Managers,
1 QC, 1 Contract Manager, 1 Accounts Receivable Manager, 0.5
Assistant
16 biostatisticians (5 MD), 12 Data managers, 2 data manager
secretaries,
4 Health economists, 2 computer scientists, 1 secretary, master
degree,
doctoral and post-doctoral students
Keywords
Clinical trials, data
management, methodology,
health economics.
• Summary:
The Biostatistics and Epidemiology Unit forms part of the
Gustave Roussy Clinical Research Division and was labeled
in 2007 as an INCa Centre for Data Handling. Its principal
roles are as follows:
1) The management and handling of data from Gustave
Roussy-promoted clinical trials from protocol to publication.
This work involves more than 65 active biomedical ongoing
research projects and 2,500 patients are recruited per year,
1,000 of which in GR.
2) Research activity related to:
- Methodological research involving the Inserm-Gustave
Roussy-CESP team «Methodology and clinical epidemiology
in molecular oncology»
- Meta-analyses
- Epidemiology of cancers
- Studies and research in Health Economics
The Biostatistics and Epidemiology Department comprises
some fifty staff (statisticians, medically qualified statisticians,
of whom one is a public health intern, data-managers, health
economists, etc.). Each year it takes on Masters degree
students for courses in biostatistics, health economics and
data management. We also supervise doctoral and postdoctoral training.
The Department participates in the training of medical and
pharmacy students, the Masters degree in Public Health
and doctoral and post-doctoral researchers in clinical and
epidemiological research, biostatistics, health economics
and data-management.
There are two university lecturers from the University of Paris-South
in the department: Marie-Cécile Le Deley and Isabelle Borget.
The Unit delivers more than 540 hours of teaching per year.
Keywords
study coordination, PhI
(Pediatrics only) to PhIV,
non-interventional study
• Objectives and mission: :
The Clinical Research Operations Unit (SORC) is responsible
for the conduct of all type of studies at Gustave Roussy
promoted by academic and industrial sponsors. Team
facilitation is essential for helping investigator site address
processes and protocol requirements. SORC coordinates all
stakeholders throughout the study and facilitates information
exchange among sponsor/Contract Research organisation
(CRO), investigators, technical facilities, research subjects, the
subject’s representatives for assuring data collection quality, in
compliance with all regulations (ICH-GCP, European Directive..
etc) and SOPs related to research involving human subjects.
In view of the growing impact of patients’ satisfaction, team
is playing a key role in a comprehension of clinical trials
environment, patient care, compliance and is dedicated contact
to ensure care coordination in this context.
Accelerating therapeutic innovation and increase patient access
to novel molecules requires major changes and challenges in
the standard paradigms of clinical trials. Our team provides
both the operational expertise and the flexibility needed not
only to ensure patient safety, accurate data and high quality
operational delivery as center of excellence but also to reduce
costs and time while increasing productivity.
90
- To ensure efficiency of patient care in clinical research
projects within all the medical committees and departments
at Gustave Roussy
- To anticipate and control increase in activity by allocating
the necessary human and technical resources
- To deliver high quality services by ensuring a Quality
Management System with ISO 9001 accreditation including
permanent training programs for all the staff
- To drive performance, financing of the structure and other
continuous improvement methodologies
• Certification
The Unit is certified as Clinical Centre Research (CRC) by
the Ministry of Health and is committed in assessment
process by national agency AERES like INSERM, CNRS and
universities.
• Activity:
Almost 400 research projects were managed by SORC in
2014, including 316 clinical trials with recruiting status.
Overall 2674 (21%) new patients have been enrolled in
these trials among 3308 (26%) new patients participating
in a biomedical research at GR (% patients with malignant
tumour treated at GR)
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Pharmacovigilance Unit
Head: Salim Laghouati
Clinical Trial Sponsoring Unit
Head: Delphine Vuillier-Legoff
Details:
Details:
Gustave Roussy, 114 rue Edouard Vaillant 94805 Villejuif, France
Tel : +33 (0) 1 42 11 61 00 - Fax +33 (0) 1 42 11 61 50
Email: salim.laghouati@gustaveroussy.fr
Tel : +33(0)1 42 11 65 42 - Fax +33(0)1 42 11 62 00
Email: Delphine.vuillier@gustaveroussy.fr
Team members:
Team members:
1 Clinical research assistant (CRA) Manager, 8 CRA, 2
Regulatory Affairs (RA) Officer,
1 Financial Manager, 0.5 RA Assistant, 2 Project Managers.
0,2 Quality Control manager,
2 Pharmacovigilance Officers,
1 Pharmacovigilance Assistant
Keywords
Keywords
pharmacovigilance,
drug safety, clinical trial,
pharmaco-epidemiology
In addition, the unit is developing a research program in
pharmacovigilance and pharmaco-epidemiology, including,
the following projects: REISAMIC (vigilance of cancer
immune therapies), VIGICAIRE (vigilance and observation
of off label use in paediatric auto-immune cytopenias) and
VIGINOM (vigilance of innovative medicines entering true life
after their marketing authorisation).
• Summary:
The Pharmacovigilance Unit (UFPV) of the Gustave Roussy
Clinical Research Division evaluates in real-time the
safety of investigational medicinal products used in more
than 70 clinical trials sponsored by Gustave Roussy and
other academic sponsors in the Ile-de-France Region. The
monitoring of investigational health products is carried out
with great care to detect possible drug side effects.
The UFPV conducts this assessment according to current
French and European regulatory requirements (in particular
the European Directive 2001/20/EC), to ensure the safety
of patients, both adults and children, included in phase I
to III trials. This applies to trials involving chemotherapy,
immunotherapy, radiotherapy, medical devices, gene or cell
therapy and trials of treatment strategy, diagnosis, surgery
and/or intensive care.
This unit comprises physicians and pharmacists and is
equipped with dedicated software (Safety Easy), which has
an interface with the EudraVigilance pharmacovigilance
data-base of the European Medicines Agency (EMA).
• Certification
In 2007 the unit obtained an ISO 9001 certificate for its
pharmacovigilance activities in clinical trials. This was
the first academic pharmacovigilance organisation to be
certified in France. Since then the UFPV certificate has been
renewed at each annual follow-up inspection performed by
AFAQ, the certifying authority (French Association of Quality
Assurance).
92
Academic Sponsor,
Clinical trials, Quality
Assurance, Patients,
Regulations
implementation of new regulations, ie the European Clinical
Trials Regulation (536/2014/EU) and the French “Loi Jardé”
‘(LOI n° 2012-300 du 5 mars 2012), in Good clinical Practices.
• Summary:
The Clinical Trial Sponsoring Unit (SPEC) is responsible for
organisaing and running national and international clinical trials
sponsored by Gustave Roussy following the European Clinical Trial
Directive (2001/20/CE). It contributes actively to the development
of clinical research by setting up innovative clinical trials allowing
patients to benefit from a high quality academic research.
Missions:
- To guarantee that studies are conducted ethically and
conform to current national and international regulations,
ensuring the right of the patients.
- To coordinate the various activities in relation with each
protocol (feasibility, risk-based monitoring, audits, logistics).
- To ensure a financial support coming from industry,
national and European grants and/or charities, following
budgets along the life of the projects.
• activity
In 2014, 86 studies managed by the SPEC were ongoing, 57
were open to recruitment and 12 were international clinical
trials (including X with North American participation). Eight
new trials were initiated in 2014 and 508 on-site monitoring
visits were performed. From a regulatory perspective, 9
initial dossiers and 45 amendments were submitted to
Competent Authorities and Ethic Committees.
• Certification
SPEC is part of the DRCI (Délégation de la Recherche
Clinique et de l’Innovation) of Gustave Roussy labeled by the
Ministry of Health.
The SPEC is currently leading the certification iso9001
process (national program for Quality Assurance and
Certification) for the entire Clinical Research Division.
In conformity with the “Plan Cancer”, patient information
sheets are systematically submitted for review prior to
the trial to the Patients Committee of the “Ligue nationale
contre le cancer”.
As a member of the French Institutional Sponsors
Coordination (CPI) , the SPEC contributes to the
93
early drug development department (DITEP)
Director : Jean-Charles Soria
Industrial Partnerships
Coordination Committee (CCPI)
Head: Eric Angevin, Alliance Manager (DITEP & DRC)
• Details:
Gustave Roussy, DITEP, 114 rue Edouard Vaillant, 94805
Villejuif, France
Tel: +33(0)1 42 11 42 91
Email: Jean-Charles.SORIA@gustaveroussy.fr
Gustave Roussy, 114 rue Edouard Vaillant,
94805 Villejuif, France
Tel: +33(0)1 42 11 50 35 – Fax: +33(0)1 42 11 65 30
Email: eric.ANGEVIN@gustaveroussy.fr
Keywords
Industrial partnership,
alliance management, scientific
collaboration, master agreement,
public-private partnering.
• Team members:
- Permanent Clinical Researchers: 12 medical oncologists
(including 2 specialists in haematology and 1 in immunotherapy),
1 radiation oncologist, 7 fellows MDs + 6 medical assistants
Clinical research staff: >100 FTEs°
- Care staff: 2 nurse managers, 26 study nurses, 5 care
assistants
- Clinical Operations staff: 2 study & coordinator managers,
33 study coordinators and data managers,
6 clinical research assistants, 2 schedulers, 2 project managers,
5 others (quality assurance, contracting, scientific officer)
The DITEP department runs the early phase trial program in adults and provides rapid access to early innovation to cancer
patients. It was re-labelled Early Phase Center (CLIP²) by the French National Cancer Institute in 2015. The team is one of the
7 international leaders in the field. The trials portfolio is composed of First-In-Human trials, phase 1 and phase 1/2 trials of
new anticancer drugs (single agents and combinations). The focus is on drugs targeting oncogenic drivers (EGFR, FGFR, MET,
NOTCH, ALK,…), immune effectors (anti-PD1/-PDL1 mAbs, ...), epigenetic (EZH2, BET,..) and metabolic (IDH,…) alterations
in solid tumours and haematological malignancies. The team played a major role in the development of several TKIs and
immunomodulators among other innovative compounds. New drug development is embedded into the Precision and Molecular
medicine program and the Immunotherapy program based on re-biopsying patient’s tumour and collecting circulating DNA
before entry into early phase trials. In the GR-sponsored MOSCATO trial (1000 patients so far), next generating sequencing,
whole exome and RNA sequencing, analysis of immunocontexture (including mutations load and search for neo-antigens) are
used to identify targetable molecular alterations for all patients and to build a large clinical-biological database for discovery
research . The GR-sponsored MATCH-R trial explores the mechanism of resistance under treatment with targeting agents
through repeated sequential biopsies for molecular profiling and generation of tumour models (in vitro cell lines, patientderived xenografts). The DITEP works in close collaboration with each organ-oriented clinical research team as well as with
the the paediatric phase I team within the CLIP². Translational research projects are implemented with UMR981 on biomarker
discovery and validation.
• Information on activity (year 2014):
- 816 patients in trials (413 patients in 82 therapeutic trials; 403 in molecular matching trials)
- 86 Trials, sponsored by industry (76), Gustave Roussy (8) and other academias (2)
- 71 trials as lead investigator
Industrials Partnerships with several pharmaceutical and biotech companies
Grants (ongoing projects): 1 PHRC, 1 INCA CLIP², 1 INCA SIRIC http://www.siricsocrate.com)
Internal collaborations (research teams at Gustave Roussy) : All organ-oriented tumour boards; Translational research
platforms; Research units: Inserm U981 (Pr André), Inserm U1030 (Pr Deutsch), Inserm U1015 (Pr Zitvogel), Inserm U1170
(Pr Solary & Dr Bernard)
94
• Permanent members of the CCPI:
Research Division representatives,
Clinical Research Division representatives
(DRC, Head of Clinical Research Operations,
Head of Gustave Roussy Sponsoring),
Early Drug Development representatives
(DITEP, Head of Early Clinical Research Operations),
General Manager of Gustave Roussy Transfert Affiliate (GRT).
• Steering Committee of the CCPI:
- Prof. Eggermont, General Director
- Prof. Solary, Director of Research
- Prof. Vassal, Director of Clinical Research Division (DRC)
- Prof. Soria, Head of the Drug Development Department (DITEP)
- Prof. Deutsch, Head of the Radiotherapy Department, Medical Director of Gustave Roussy Transfert
• expertises:
The Industrial Partnerships Coordination Committee (CCPI) is created since 2011 to facilitate any kind of collaborative
initiative between Gustave Roussy teams and industrials in oncology. The CCPI permanent members are in charge, each
in their field of responsibility, to streamline interactions with pharmaceutical or biotech companies for the implementation
of fruitful, well-balanced and long-lasting collaborations regarding innovative drugs or biomarkers developments, biology,
imaging or any other expertise on site in clinical and translational research.
• Tasks and goals
- Facilitation of contacts between Gustave Roussy teams and industrials
- Preparation and elaboration of agreements and contracts (e.g. alliance & master agreement)
- Implementation and follow-up of mutual commitments with industrial partners
- Support to the Gustave Roussy teams involved in industrial collaborations
- Reporting to the CCPI steering committee for strategic orientations and decisions
95
core
fa c i l i t i e s
CNRS UMS3655 - INSERM US23 MOLECULAR ANALYSIS, MODELlING AND IMAGING
OF CANCER DISEASE
Immune Monitoring Laboratory in Oncology
Platform director: Nathalie Chaput
Research Unit director: Jean-Yves Scoazec
Details:
Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif cedex
Tel.: +33(0)1 42 11 56 55
e-mail: Nathalie.CHAPUT@gustaveroussy.fr
Immune Monitoring Laboratory in Oncology: Nathalie Chaput
Genomics: Nathalie Droin, Ludovic Lacroix
platform members:
- Permanent researchers: 1 (CDI de mission Gustave Roussy)
- Faculty members:1/4
- Technical staff: 2 (CDI de mission Gustave Roussy
et 1 CDD Gustave Roussy)
- PhD students: 2
- Others: 1 résident sénior (MD, Gustave Roussy),
1 PH-chercheur Gustave Roussy 1/4
Circulating tumour cells: Françoise Farace
Bioinformatics: Daniel Gautheret
Preclinical evaluation platform: Patrick Gonin
Keywords
Metabolomics: Guido Kroemer
Immunology,
Immunopathology,
Immunotherapy, Translational
medicine, Vaccines
Imaging and cytometry platform: Corinne Laplace-Builhé
Proteomics: Vasily Ogryzko
Biological resource centre: Jean-Yves Scoazec
Histopathology: Jean-Yves Scoazec
• EXPERTISES AND SERVICES:
Translationnal research in oncoimmunology and
immunotherapy. We aim at defining predictive markers of
efficacy/toxicity of immunomodulatory agents according to
specific tumour/host immune and molecular interactions.
Our goal is to improve our knowledge and understanding
of the immune system in cancer bearing hosts, to identify
relevant new biomarkers and to develop new therapeutic
targets.
• 3 patents
TOP 5 PUBLICATIONS
Br J Cancer. 2013
Dendritic Cell-derived Exosomes as Maintenance Immunotherapy after First Line
Chemotherapy in NSCLC.
Besse B, Charrier et al. OncoImmunology (in press) 2015
Phase I clinical trial combining imatinib mesylate and IL-2: HLA-DR(+) NK cell levels correlate
with disease outcome.
Chaput N et al.
Oncoimmunology. 2013
Regulation of CD4(+)NKG2D(+) Th1 cells in patients with metastatic melanoma treated with
sorafenib: role of IL-15Rα and NKG2D triggering.
Chaput N et al.
Cancer Res. 2014
Experience in daily practice with ipilimumab for the treatment of patients with metastatic
melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved
survival.
Delyon J et al.
Ann Oncol.2013
Tumour-infiltrating CD68+ and CD57+ cells predict patient outcome in stage II-III colorectal
cancer.
Chaput N, et al.
98
99
Genomics
Platform directors: Nathalie Droin, Ludovic Lacroix
Circulating tumour cells platform
Platform director : Françoise Farace
Details:
Details:
Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif cedex
Tel.: +33(0)1 42 11 50 82
e-mail :
Research : Nathalie.DROIN@gustaveroussy.fr
Clinical Research: ludovic.LACROIX@gustaveroussy.fr
Tel.: +33(0)1 42 11 51 98
e-mail: Francoise.FARACE@gustaveroussy.fr,
platform members:
4 and 6 for clinical (research team)
- PhD students: 2
platform members:
Keywords
Next Generation Sequencing
– HiSeq2000-MiSeq-PGM – Gene
Expression – CGH – SNP Array
– Digital PCR – Research and
Clinical Research.
The GustaveRoussy’s Genomics Platform provides
comprehensive genomic services to the scientific community
and for Clinical Research including 2 dedicated team,
One team for the research project for the scientific (N.Droin)
and one ISO 9001 certified team driving analysis for clinical
trials and research (L.Lacroix).
Plateform activities and services included :
-Advice and assistance with the experimental design to
allow the use of the best technology to address the scientific
question
- Advice and assistance with the preparation of samples/
quality control
- Production of Agilent microarrays (Gene Expression,
miRNA, CGH comparative genomic hybridisation)
- Production of Affymetrix microarrays (SNP Arrays, Gene
Expression Arrays)
- High-throughput sequencing with HiSeq2000 (Whole
genome, exome, RNA-seq, ChIP-seq)
- Target resequencing or Targeted RNAseq with MiSeq,
AmpliSeq on MiSeq and PGM
- Open access after reservation to the following
equipment (research team): Nanodrop spectrophotometer
(quantification of nucleic acids), Bioanalyser (quality control
for nucleic acids or proteins), real-time PCR apparatus (96well plates and Taqman Low-Density Array (TLDA) cards),
Covaris S220
- The Genomics Platform explores, validates, optimises, and
implements new technologies (Fluidigm), methods to make
them available to the scientific community.
- For Clinical Activity, weekly bach of analysis for Gene panel
sequencing or targeted RNAseq (PGM), SNParray, Q-PCR,
Digital PCR for patient included in clinical trials and based
on Tissue samples as well as Circulating DNA.
• equipment:
- 2 PGM IonTorrent + 3 OneTouch, séquençage NGS (Life
Technologie)
- Plateforme Micro Array (Affymetrix)
- 1 DD PCR Stilla (en développement)
- Extracteur EZ1 (Qiagen)
- 1 bloc Viia7 Q-PCR 96puits (Life Technologie)
- 8 blocs PCR (96puits)
- pre-analytics: 2 bioanalyseur 2100 (Agilent) ; 2 nanodrop
ND-1000 ; 1 QuBIT (Life Technologies) ; 1 ultra sonicateur
Covaris S220 ; 1 ultra sonicateur Covaris E220
- PCR-Q: TaqMan SDS 7900 HT ; QuantStudio® 3D Digital
PCR System (Life Technologies) ; Système BioMark HD et
module C1 (Fluidigm)
- Microarrays: Scanner Microarrays - Agilent
- High throughput sequencing: Robot Bravo (Agilent) ;
Robot SpriWorks (Beckman) ; HiSeq2000 (Illumina) ; MiSeq
(Illumina)
Genomes in the clinic: the Gustave Roussy Cancer Center experience.
Lacroix L, Boichard A, André F, Soria JC.
Curr Opin Genet Dev. 2014 Feb;24:99-106.
MET genetic abnormalities unreliable for patient selection for therapeutic intervention in
oropharyngeal squamous cell carcinoma.
Lacroix L, Post SF, Valent A, Melkane AE, Vielh P, Egile C, Castell C, Larois C, Micallef S,
Saulnier P, Goulaouic H, Lefebvre AM, Temam S.
PLoS One. 2014 Jan 17;9(1):e84319.
The platform is in charge of the analysis of very rare cells
in peripheral blood such as circulating tumour cells (CTCs)
and circulating endothelial cells (CECs) and the detection of
plasmatic biomarkers such as angiogenic factors. CTCs and
CECs (including mature CECs and circulating endothelial
progenitors (CEPs)) are enumerated and characterised using
either standardized approaches such as the CellSearch, or
more original techniques developed in the laboratory. Studies
on the clinical value of these cell populations are conducted
in the context of monocentric or multicentric clinical trials. In
collaboration with European or French consortiums the platform
evaluate and develop novel techniques for characterised these
cell populations.
The CTC team is more focused on the molecular characterization
of CTCs in non-small cell lung cancer (NSCLC) and prostate cancer
(PCa). Original approaches have been established to characterise
CTCs isolated on filters by combining immunofluorescence
staining and FISH or by laser-microdissection of CTCs and
their analysis at the single cell level. In NSCLC, research are
focused on the characterisation of CTCs harbouring predictive
biomarkers such as ALK and ROS1 rearrangement or activating
EGFR mutations as well as the analysis of acquired resistance
mutations to tyrosine kinase inhibitors in CTCs. In PCa, the
project is oriented on the characterization of CTCs harbouring
key prostate biomarkers such androgen receptor (AR)
amplification and ERG translocation, and the identification of
novel biomarkers by exome sequencing of CTCs at the single cell
level. Patient derived xenografts models starting with CTCs are
also established in order to study and characterise the tumour
initiating cell capacity of CTCs.
• equipment:
- Main CTC enrichment and detection systems:
. CellSearch system
. ISET device
. Siemens microfuidic filtration system
. Parsortix microfluidic system
- Epi-fluorescence microscope Eclipse Ti Nikon
- Ariol scanning system with a Leica DM6000 B microscope
- Systems for single cell isolation:
. Lasermicrodissector (Leica)
. Puncher system with a Nikon microscope
- Facscalibur (Becton Dickinson)
- Thermal Cycler Applied Biosystems 2720)
- Thermal Cycler Veriti 96-Well (X2)
• 2 patents
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive
NSCLC patients.
Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L, Soria JC.
Ann Oncol. 2015 Aug 12. pii: mdv319.
Keywords
circulating tumour cells (CTCs), circulating
endothelial cells (CECs), circulating endothelial
progenitor cells (CEPs), predictive biomarkers,
biomarkers of resistance to targeted therapies, CTCderived xenografts models.
Molecular screening for a personalized treatment approach in advanced adrenocortical cancer.
De Martino MC, Al Ghuzlan A, Aubert S, Assié G, Scoazec JY, Leboulleux S, Do Cao C, Libè R,
Nozières C, Lombès M, Pattou F, Borson-Chazot F, Hescot S, Mazoyer C, Young J, Borget I,
Colao A, Pivonello R, Soria JC, Bertherat J, Schlumberger M, Lacroix L, Baudin E.
J Clin Endocrinol Metab. 2013 Oct;98(10):4080-8.
Somatic RAS mutations occur in a large proportion of sporadic RET-negative medullary thyroid
carcinomas and extend to a previously unidentified exon.
Boichard A, Croux L, Al Ghuzlan A, Broutin S, Dupuy C, Leboulleux S, Schlumberger M, Bidart
JM, Lacroix L.
J Clin Endocrinol Metab. 2012 Oct;97(10):E2031-5.
100
High Level of Chromosomal Instability in Circulating Tumor Cells of ROS1-Rearranged NonSmall-Cell Lung Cancer.
Pailler E, Auger N, Lindsay CR, Vielh P, Islas-Morris-Hernandez A, Borget I, Ngo-Camus M,
Planchard D, Soria JC, Besse B, Farace F.
Annals Oncol 2015 Jul;26(7):1408-15.
Detection of Circulating Tumor Cells Harboring a Unique ALK-Rearrangement in ALK Positive
Non-Small-Cell Lung Cancer.
Pailler, E., Adam, J., Barthélémy, A., Oulhen, M., Auger, N., Valent, A., Borget, I., Planchard, D.,
Taylor, M., André, F., Soria, J.C., Vielh, P., Besse, B. and Farace, F.
J Clin Oncol 31(18):2273-81, 2013.
Taylor, M., Billiot, F., Marty, V., Rouffiac, V., Cohen, P., Tournay, E., Opolon, P., Louache, F., Vassal,
G., Laplace-Builhe, C., Vielh, P. Soria, J.C and Farace, F.
Cancer Discov 2, 434-449, 2012.
Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients
treated with first-line chemotherapy and bevacizumab.
Malka, D., Boige, V., Jacques, N., Vimond, N., Adenis, A., Boucher, E., Pierga, J.Y., Conroy, T.,
Chauffert, B., Francois, E., Guichard, P., Galais, M.P., Cvitkovic, F., Ducreux , M. and Farace, F.
Ann Oncol 23, 919-927, 2012.
Efficacy, Safety, and Biomarkers of Single-Agent Bevacizumab Therapy in Patients with
Advanced Hepatocellular Carcinoma.
Boige, V., Malka, D., Bourredjem, A., Dromain, C., Baey, C., Jacques, N., Pignon, J.P., Vimond,
N., Bouvet-Forteau, N., De Baere, T., Ducreux, M. and Farace, F.
The Oncologist. 17(8):1063-72, 2012.
101
Bioinformatics Platform
Platform leader: Daniel Gautheret
Deputy platform leader: Guillaume Meurice
Preclinical Evaluation Platform
Platform director: Patrick Gonin
Details:
Tel.: +33(0)1 42 11 40 39
e-mail: Patrick.GONIN@gustaveroussy.fr
Details:
Gustave Roussy, Bioinformatics Core Facility,
Tel. office: +33(0)1 42 11 41 12
e-mail: daniel.gautheret@gustaveroussy.fr
e-mail: Guillaume.Meurice@gustaveroussy.fr
platform members:
- Permanent Researchers: 1 Gustave Roussy
- Technical staff: 11 Gustave Roussy, 3 Inserm.
ONGOING SCIENTIFIC AND INDUTRIAL
platform members:
- PhD students : 1
- Others : 5
Keywords
NGS, genomic, RNA-Seq,
Whole Exome, precision
medecine
This core facility offers support to all cancer research projects
requiring bioinformatics, either in academic labs or clinical
research groups. Our main expertise is high throughput genome
sequence analysis for human molecular biology and precision
medicine.
Our services range from complete in-house support of
bioinformatics projects, from design to analysis, to providing labs
with the required bioinformatics infrastructure and software, or
to coaching students and interns involved in bioinformatics tasks.
Furthermore, we develop, run and distribute custom pipelines
integrating state of the art software for the following tasks:
- microarray gene expression analysis (gene and microRNA,
Agilent and Affymetrix)
- microarray CGH analysis (Agilent and Affymetrix)
- NGS data analysis (Ion Torrent, HiSeq, MiSeq)
• Mutation/short indel detection (Whole Exome and RNASeq)
• Copy number alteration / LOH analysis
• Structural variation (large deletion)
• RNASeq differential analysis
• Fusion Event detection (RNASeq)
• ChipSeq analysis
• Metagenomic
• equipment:
Our Bioinformatic core facility is using two computing cluster :
- 4 nodes (each node has 24 core, 96 Go RAM) with 100 To high
performances hard drive.
- 16 nodes (each node has 24 core, 128GB RAM), with 1 NFS
partition of 75 To and 1 Beegfs partiton of 150Tb . This cluster
also have a fat node of 32 cores and 1024 Go RAM.
We are archiving the data from all project using an Active Circle
server (LTO magnetic tape with 16 To of high capacity hard drive).
The PFEP is the platform for preclinical studies, specialised in the
development of animal models for understanding the implication
of target genes in carcinogenesis and for assessing pre-clinical
strategy of anticancer drugs or combinations.
The PFEP is a platform with an official approval (license E 94-07611). All facilities and studies are in compliance with the French
decree and acts transposing European Directive 2010/63. All
studies are also assessed and approved by the officially accredited
Animal Care and Use n°26 prior starting.
The PFEP provide researchers, clinicians and outside companies
with the means and skills needed to conduct their research
programs using live animals. It ensures, as the law requires
it: checking training and competence of animal users and their
training as appropriate. It monitors and trace the welfare of the
animals, thanks to its animal welfare body, and, when necessary,
veterinary care.
It also ensures the health monitoring, prophylactic or curative
treatment, the supply of anaesthetic and all required drugs, all
surgeries, autopsies, diagnostic opinions and is implementing all
or part of experimental protocols using animals.
The platform thus ensures the implementation of all or part of
the in vivo preclinical studies, and carries out methodological
developments based on the needs of researchers.
- Laboratory Animal Science and medicine, veterinary care, routine
care and health monitoring of the animals (including monitoring
of breeding, and performing cryopreservation of eggs and sperm).
- realisation of experimental protocols and procedures (feasibility,
development and implementation of ad hoc surgical procedure,
genotyping, xenografts (all types)).
- realisation of pathological and histological examinations
- Coordination of the CapSud Network of the Animal Facilities of
Université Paris Sud
- Animation, coordination and Chairmanship of the Ethics
Committee in Animal Experimentation 26 (EAEC 26).
• equipment:
Premises (700 sq m) are organised in different sectors, and
all mice are housed in individually ventilated cages (n=4500)
or insulators (500 cages, also for breeding of specific immune
deficient mice). All experimental rooms are equipped with
mobile gas anaesthesia machines (n=6). Platform includes
as well two research grades irradiators (X-Rays) for mouse
aplasia or irradiation.
• Scientific collaboration with Genopole CERFE
• Network Coordination MRM Université Paris Sud.
TOP 5 PUBLICATIONS
TOP 5 PUBLICATIONS
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
Saliba J. et al.
Nat Genet 2015; ePub ahead of print.
Correction of the FSHD Myoblast Differentiation Defect by Fusion With Healthy Myoblasts.
Dib C. et al.
J Cell Physiol. 2015; ePub ahead of print.
Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle
progression and transformation in human breast cancer cells.
Bach, AS. et al.
Oncotarget. 2015; ePub ahead of print.
A simplified interventional mapping system (SIMS) for the selection of combinations of targeted
treatments in non-small cell lung cancer.
Lazar V. et al.
Oncotarget. 2015; 6:14139-52.
Comparative analysis of primary tumour and matched metastases in colorectal cancer
patients: Evaluation of concordance between genomic and transcriptional profiles.
Vignot S. et al.
Eur J Cancer. 2015; 51:791-9.
102
Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor
CHCHD4.
Modjtahedi N, Hangen E, Gonin P, Kroemer G.
Cell Cycle. 2015 Sep 2;14(17):2743-2747.
Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.
Hangen E, Féraud O, Lachkar S, Mou H, Doti N, Fimia GM, Lam NV, Zhu C, Godin I, Muller
K, Chatzi A, Nuebel E, Ciccosanti F, Flamant S, Bénit P, Perfettini JL, Sauvat A, BennaceurGriscelli A, Ser-Le Roux K, Gonin P, Tokatlidis K, Rustin P, Piacentini M, Ruvo M, Blomgren K,
Kroemer G, Modjtahedi N.
Mol Cell. 2015 May 20. pii: S1097-2765(15)
p19(INK4d) Controls Hematopoietic Stem Cells in a Cell-Autonomous Manner during Genotoxic
Stress and through the Microenvironment during Aging.
Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, Villeval JL, Louache F, Gonin
P, Debili N, Plo I, Vainchenker W, Gilles L, Raslova H.
Stem Cell Reports. 2014 Dec 9;3(6):1085-102.
CXCR4 inhibitors selectively eliminate CXCR4 expressing human acute myeloid leukemia cells
in NOG mouse model.
Yanyan Zhang, S Patel, H Abdelouahab, M Wittner, C Willekens, i Shen, A Betems, V Joulin, P
Opolon, O Bawa, F Pasquier, M Ito, N Fujii, P Gonin, E Solary, W Vainchenker, P Coppo, S De
Botton, F Louache.
Cell Death Dis 2012 Oct 4;3:e396.
Characterization of a large panel of patient-derived tumor xenografts representing the clinical
heterogeneity of human colorectal cancer.
Sylvia Julien, Ana Merino-Trigo, Ludovic Lacroix, Marc Pocard, Diane Goéré, Pascale Mariani,
Sophie Landron, Ludovic Bigot, Fariba Némati, Peggy Cuilliere-Dartigues, Louis-Bastien
Weiswald, Denis Lantuas, Loïc Morgand, Emmanuel Pham, Patrick Gonin, et al.
Clin Cancer Res. 2012 Oct 1;18(19):5314-28.
103
Metabolomics
Platform director: Guido Kroemer
Imaging and Cytometry Platform
Platform director: Corinne Laplace-Builhé
Details:
Details:
Gustave Roussy, Metabolomics Plaform,
Tel.: +33(0)1 42 11 60 41
e-mail: Kroemer@orange.fr
Tel.: +33(0)1 42 11 66 72
e-mail: Corinne.LAPLACE@gustaveroussy.fr
platform members:
platform members:
- Technical: 2 Gustave Roussy, 1 Inserm
The platform has the capacity of providing all means for
the entire workflow, from extraction of metabolites from
biological samples to their metabolomic analysis and their
biostatistic and biomathematical integration.
Non-targeted metabolomic profiling is performed by means
of a high-resolution mass spectrometer coupled to an ultrahigh performance liquid chromatograph (UHPLC).
Targeted metabolomic analyses relies on the MRM (multiple
reaction monitoring) technique, after UHPLC or gas
chromatography, depending on the specific physicochemical
properties of the metabolite of interest
- Unbiased profiling of biological samples by UHPLC/QTOF
- Semi-quantitative analysis of large arrays of endogenous
metabolites
- Structural exploration by high-resolution mass
spectrometry (HRMS)
- Quantitative analysis of candidate metabolites
- Follow-up analyses throughout a project
- Assistance in experimental design
- Development of specific extraction protocols
- Statistical analysis, mathematical modelling, integration
of metabolic data
- Interpretation of data in their biological context
• equipment:
The platform is equipped with three distinct mass
spectrometer/chromatography combinations
- UHPLC 1260 Binary Pump Agilent - QTOF 6520 Agilent for
the profiling and identification of metabolites byHRMS
- UHPLC 1260 Binary Pump Agilent - QQQ 6410 Agilent for
the targeted quantification of metabolites after liquid phase
chromatography
- GC 7890A - QQQ 7000A Agilent for the targeted quantification
of metabolites after gas chromatography
104
- Permanent researchers: 2 Gustave Roussy, 2 external ressources
- Technical: 1 Gustave Roussy, 2 Inserm
The Imaging and Cytometry platform strives to provide
biomedical scientists and industry with equipment at the
cutting edge of technology in various fields of biomedical
imaging and cytometry (confocal microscopy and
multiphoton, flow cytometry and cell sorting, in vivo photon
imaging). The platform offers the expertise and technological
support needed for the realisation of scientific projects and
supports hands-on multidisciplinary training for the use of
instruments.
- Theoretical and practical training in photonics, multiphoton
imaging and flow cytometry
- Advice on implementation of imaging and Cytometry experiments
- Assays and assistance on instruments use
- Supervision or advice on the acquisition and analysis of data
- Aid to the analysis, interpretation and presentation of data and
images
- Development of new protocols or new technical updates
- Technical maintenance of instruments
- Technological developments
The PFIC is strongly involved in instrumental development
projects for high resolution imaging in patients through
industrial projects and academic collaboration, and
especially for the assessment of confocal microendoscopy
and optical coherence tomography (OCT), for intraoperative
tumour resection margins.
• equipment:
The platform operates on four axes (cell and molecular
imaging, small animal imaging, cytometry and cell sorting
and R&D for clinical transfer of photon imaging).
The available equipment consists in 16 instruments
of which 70% were renewed during the past 4 years,
with 2 new machines installed mid- 2015. (One 18
colours Flow cytometer and one small-animal imager
(fluorescence&bioluminescence) attached to 3D scanner)
105
Integrated Biology Platform - Proteomics
Platform director: Vasily Ogryzko
Biological Resource Centre
Platform director: Jean-Yves Scoazec
Details:
Details:
Tel.: +33(0)1 42 11 65 25
e-mail: Vasily.OGRYZKO@gustaveroussy.fr
Gustave Roussy,
Tel. office: +33(0)1 42 11 51 31
e-mail: GD-CRB@gustaveroussy.fr
platform members:
platform members:
Keywords
biological resources – frozen
tissues – blood - nucleic acids
High-throughput protein analysis technology is a tool
complementary to genomics, being better suited for an
analysis of other than transcription levels of regulation of
gene activity, thus providing new perspectives in development
of diagnostic and therapeutic tools. As a part of a global
project of analysis of complex biological samples, one of
the ultimate aims of the Platform is identification cancerspecific markers.
The Proteomics Platform is accessible for all academic
groups, internal or external to Gustave Roussy. It offers a
set of technologies for proteomic analysis, from protein
identification to comparison of proteomes, to analysis of posttranslational modifications, to protein-protein interaction
partners identification up to primary bioinformatic analysis.
The analysis system Q-Exactive Orbitrap was launched
in 2014. This system allows for a quantitative proteomic
profiling of complex protein samples, as well as to study
post-translational modifications (acetylation, methylation,
phoshorylation, ubiquitinylation etc), and to perform
targeted analyses of proteomes and the Top-Down analysis
of proteins.
· Definition of optimal experimental design
· Collaboration with those responsible for the projects
concerned
· Advice concerning the structure and setting up of projects
· Advice and assistance with the preparation of samples/
quality control
· Protein identification
· Comparison of proteomes (SILAC based or label-free)
· Analysis of post-translational modifications
· Targeted proteomics
· Primary bioinformatic analysis
• equipment:
Mass-Spectrometry Hardware:
An LC-MS/MS system for low scale and low resolution
proteomic analysis:
· Agilent API MALDI
· Agilent 6340 ion trap with ECD and CHIP cube
· Agilent Nano HPLC 1200
· Agilent Chip-Cube
· Agilent Off-Gel fractionator
Last generation LC-MS/MS system for high capacity and
resolution proteomic analysis (label free quantitative
proteomics, targeted proteomics, Top-Down analysis of
proteins):
· ThermoFisher Orbitrap Q-Exactive
· ThermoFisher EASY-nLC 1000
Proteomics Software Packages:
· Agilent Server Spectrum Mill
· ThermoFisher Server Proteome Discoverer
· ThermoFisher Server SIEVE 2.0
· ThermoFisher Server PINPOINT 1.2
· ThermoFisher Server ProSightPC 2.0
+ Small laboratory equipment
The Biological Resource Centre has the mission to collect,
prepare and store biological samples (cells, tissues, fluids,
nucleic acids) used in clinical or experimental research
programs, with academic or industrial partners.
The Biological Resource Centre contains 3 modules (CRB
Tissu for cell and tissue samples, ET EXTRA for fluids and
Predisposition for blood and derived products from patients
with predisposition syndromes).
Samples come from patients managed in Gustave Roussy,
enrolled in clinical trials or considered informative by
clinicians or pathologists. All patients have signed an
informed consent. The Biological Resource Centre is
equipped for the collection, preparation (pre-analytical
techniques, microdissection) and storage of frozen material
and FPPE tissue samples. The transfer of material to
research programs is made on the basis of a justified
request, after verification of the patient consent.
A quality management system has been implemented. The
Resource Centre is certified NF CS96-900 since 2014.
TOP 5 PUBLICATIONS
The politics of the Biological Resource Center is to be cited in Material and Methods or to be
acknowledged in all papers based on biological material obtained from its collections.
106
107
BioCELL platform (PACRI) UMR 1138 INSERM
Histopathology
Platform director: Jean-Yves Scoazec
Research director: Guido Kroemer
Platform leader: Oliver Kepp
Details:
Details:
Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif
Tel. office: +33(0)1 42 11 44 67
e-mail: GD-HCP@gustaveroussy.fr
Gustave Roussy, BioCell platform,
Tel. office: +33(0)1 42 11 45 16
e-mail: oliver.kepp@gustaveroussy.fr
platform members:
platform members:
- PhD students : 3
- Others : 1
Keywords
histopathology–
immunohistochemistry – FISH
– microdissection – TMAtranslational research
The team is in charge of the whole spectrum of morphological
techniques for cell and tissue analysis in the context of
translational research programs (for academic or industrial
partners) and precision medicine. This includes conventional
histology,
histochemistry,
immunohistochemistry
(immunoperoxidase and immunofluorescence) and FISH.
The facility is also equipped to perform tissue microdissection
and to construct tissue microarrays (TMA). Pathologists and
cytogeneticists are available to analyse and interpret the
results and to provide complete reports.
The facility has a quality management system and is in
process of certification.
Keywords
High throughput compound
and siRNA screening; imaging;
biosensors; cell death
• Information on Knowledge Transfer Activities of the research team:
- Number of patents since 2010 (indicating those with license): 0
- List of industrial partnerships and / or consultancies since 2010: Air Liquide ; GSK oncology ; Lytix Biopharma ;
Genentech ; PharmaMar ; Bayer Healthcare
- «spin-off / startups / biotech» from your team: 0
Built within the Paris Alliance of Cancer Research
Institutes (PACRI), the BioCELL platform works in
concert with INSERM UMR1138 “APOPTOSIS, CANCER
& IMMUNITY” to investigate the molecular and cellular
mechanisms of cell stress and cell death. The mode of
cellular stress and death that is evoked during cancer
treatment has profound therapeutic implications. A
systematic search has been launched to identify molecular
switches that “decide” which particular cell stress or cell
death subroutine is preferentially executed. In addition,
cancer cell death modalities and their impact on the
immune system are analysed in a systematic fashion to
develop strategies that improve the chances of therapeutic
success.
The BioCELL platform at Gustave Roussy is used as a
hub to conduct screening approaches, as it offers fully
automated cell biology workflows that allow for the
phenotypic screening of large-scale compound and
siRNA libraries necessary to conduct systems biology
oriented research. The unique design of the platform
allows for extremely flexible assay design and multiplexing
as it integrates automated cell culture and compound
management with three different fully automated high
content analysis systems via an industrial robot.
TOP 5 PUBLICATIONS
A simplified interventional mapping system (SIMS) for the selection of combinations of targeted
treatments in non-small cell lung cancer.
Lazar V, Rubin E, Depil S, Pawitan Y, Martini JF, Gomez-Navarro J, Yver A, Kan Z0, Dry JR,
Kehren J, Validire P, Rodon J, Vielh P, Ducreux M, Galbraith S, Lehnert M, Onn A, Berger R,
Pierotti MA, Porgador A, Pramesh CS, Ye DW, Carvalho AL, Batist G, Le Chevalier T, Morice
P, Besse B, Vassal G, Mortlock A, Hansson J, Berindan-Neagoe I, Dann R, Haspel J, Irimie A,
Laderman S, Nechushtan H, Al Omari AS, Haywood T, Bresson C, Soo KC, Osman I, Mata H,
Lee JJ, Jhaveri K, Meurice G, Palmer G, Lacroix L, Koscielny S, Eterovic KA, Blay JY, Buller
R, Eggermont A, Schilsky RL, Mendelsohn J, Soria JC, Rothenberg M, Scoazec JY, Hong WK,
Kurzrock R.
Oncotarget. 2015;6:14139-52.
Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive
non-small-cell lung cancer.
Pailler E, Adam J, Barthélémy A, Oulhen M, Auger N, Valent A, Borget I, Planchard D, Taylor M,
André F, Soria JC, Vielh P, Besse B, Farace F.
J Clin Oncol. 2013;31:2273-81.
Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote
escape from T-cell-mediated lysis.
Akalay I, Janji B, Hasmim M, Noman MZ, André F, De Cremoux P, Bertheau P, Badoual C, Vielh
P, Larsen AK, Sabbah M, Tan TZ, Keira JH, Hung NT, Thiery JP, Mami-Chouaib F, Chouaib S.
Cancer Res. 2013;73:2418-27.
Taylor M, Billiot F, Marty V, Rouffiac V, Cohen P, Tournay E, Opolon P, Louache F, Vassal G,
Laplace-Builhé C, Vielh P, Soria JC, Farace F.
Cancer Discov.2012;2:434-49.
PARP1 impact on DNA repair of platinum adducts: preclinical and clinical read-outs.
Olaussen KA, Adam J, Vanhecke E, Vielh P, Pirker R, Friboulet L, Popper H, Robin A, Commo F,
Thomale J, Kayitalire L, Filipits M, Le Chevalier T, André F, Brambilla E, Soria JC.
Lung Cancer. 2013;80:216-22.
108
TOP 5 PUBLICATIONS
- Unsaturated fatty acids induce non-canonical autophagy.
Niso-Santano, M., Malik, S.A., Pietrocola, F., Bravo-San Pedro, J.M., Marino, G., Cianfanelli, V.,
Ben-Younes, A., Troncoso, R., Markaki, M., Sica, V., et al.
The EMBO journal 2015; 34, 1025-1041.
- Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.
Lissa, D., Senovilla, L., Rello-Varona, S., Vitale, I., Michaud, M., Pietrocola, F., Boileve, A., Obrist,
F., Bordenave, C., Garcia, P., et al.
Proceedings of the National Academy of Sciences of the United States of America 2014; 111,
3020-3025.
- Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of
chemotherapy.
Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D.P., Adam, J., Vitale, I., Goubar, A.,
Baracco, E.E., Remedios, C., et al.
Nature medicine 2014; 20, 1301-1309.
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