Trouble Makers - Dana-Farber Cancer Institute
Transcription
Trouble Makers - Dana-Farber Cancer Institute
Spring/Summer 2013 Research and Care at Dana-Farber Cancer Institute Trouble Makers picking out the mutations that matter Including the 2012 Annual Report PLUS: multiple myeloma research • tech shortcuts • treating young adults Dana-Farber Cancer Institute ... “Dedicated to discovery ... committed to care” is the mission of Dana-Farber Cancer Institute (DFCI), described as one of the world’s premier cancer centers by the National Cancer Institute. Founded in 1947 by Sidney Farber, MD, DanaFarber is renowned for its unique blend of basic and clinical research and for using its discoveries to improve the treatment of adults and children with cancer and related diseases. It is a founding member of the Dana-Farber/Harvard Cancer Center – one of 41 nationally designated Comprehensive Cancer Centers. A teaching affiliate of Harvard Medical School, Dana-Farber is also one of 21 federal Centers for AIDS Research in the United States, and is consistently ranked one of the top cancer centers in the country by U.S. News & World Report. In addition, it has earned “Magnet” status for excellence in nursing. Dana-Farber partners with Brigham and Women’s Hospital to deliver care for adults with cancer through Dana-Farber/ Brigham and Women’s Cancer Center. It also has a long standing alliance with Boston Children’s Hospital to care for pediatric cancer patients through Dana-Farber/Children’s Hospital Cancer Center. By bringing together the strengths of three world-class institutions, these partnerships provide an exceptional level of care for cancer patients and their families. Spring/Summer 2013 Volume 22, Number 1 President and CEO, Dana-Farber Cancer Institute Edward J. Benz Jr., MD Chief Financial Officer and Assistant Treasurer Karen Bird, MPH Chair, Psychosocial Oncology and Palliative Care Susan D. Block, MD Senior VP and General Counsel Richard S. Boskey, Esq. Chief Medical Officer Craig Bunnell, MD, MPH, MBA Senior VP for Experimental Therapeutics George Demetri, MD Senior VP for Research Beverly Ginsburg Cooper, MBA Chair, Medical Oncology James D. Griffin, MD Chair, Radiation Oncology Jay R. Harris, MD Senior VP for Human Resources Deborah Hicks, MA Chief Quality Officer Joseph O. Jacobson, MD, MSc Chief Clinical Research Officer Philip W. Kantoff, MD Senior VP for Experimental Medicine Lee M. Nadler, MD Chair, Pediatric Oncology Stuart H. Orkin, MD Senior VP for Institute Operations Maria Papola, MHA Senior VP for Development Susan S. Paresky, MBA Executive VP and Chief Operating Officer Dorothy E. Puhy, MBA Senior VP for Patient Care Services, Chief Nurse Patricia Reid Ponte, RN, DNSc, FAAN Chief Scientific Officer Barrett J. Rollins, MD, PhD Chief of Staff Emeritus Stephen E. Sallan, MD Chief of Staff, Senior VP of Medical Affairs, Director of Regional Development, and Director of Center for Global Cancer Medicine Lawrence N. Shulman, MD ... and the Jimmy Fund Senior VP for Communications Steven R. Singer, MPA The Jimmy Fund (www.JimmyFund.org) solely supports Boston’s Dana-Farber Cancer Institute, raising funds for adult and pediatric cancer care and research to improve the chances of survival for cancer patients around the world. This year celebrates the 60th anniversary of the Jimmy Fund and Boston Red Sox relationship, and represents one of the most remarkable partnerships between a team and a charity in the history of professional sports. The Jimmy Fund is also the official charity of the Massachusetts Chiefs of Police Association, the Pan-Massachusetts Challenge, and the Variety Children’s Charity of New England. Since 1948, the generosity of millions of people has helped the Jimmy Fund save countless lives and reduce the burden of cancer for patients and families worldwide. Follow the Jimmy Fund on Facebook (www.facebook.com/thejimmyfund) and on Twitter (@TheJimmyFund). 10% of all designated gifts supports our Faculty Research Fund to advance Dana-Farber’s research mission. ® Chief Surgical Officer Scott J. Swanson, MD Chief of Radiology Annick D. Van den Abbeele, MD Editor Michael Buller Design John DiGianni Associate Editor Robert Levy Managing Editor Eric Schuller Production Jacqueline Czel, Jessica Walker Photographer Sam Ogden Writers Christine Cleary, Elizabeth Dougherty, Naomi Funkhouser, Richard Saltus, Saul Wisnia Additional Photography Getty Images, Manalis Lab MIT, NCI Visuals, Aarron Washington Paths of Progress is published twice a year by Dana-Farber Cancer Institute. If you have any comments or would like to be removed from the mailing list, please contact: Michael Buller, Editor, Paths of Progress Dana-Farber Cancer Institute, Dept. of Communications 450 Brookline Ave., OS301 Boston, MA 02215 617-632-4090 pathsofprogress@dfci.harvard.edu Copyright © 2013 Dana-Farber Cancer Institute. All rights reserved. CONTENTS Features Departments 10 Trouble Makers 3 Around the Institute In tumor cells with hundreds of gene mutations, investigators must identify which ones are guilty of driving cancer growth. 16 Man on a Mission Ken Anderson, MD, has helped transform multiple myeloma from an often fatal disease to, in many cases, a chronic, manageable illness. 20 Science Illustrated Gene mutations or abnormalities can spur cancer growth, but these same mutations may leave cells vulnerable to cleverly designed therapies. A free nutrition app for your iPhone, 20 years of pediatric survivorship, and more news from Dana-Farber. 7 Six Questions for ... Craig Bunnell, MD, MPH Dana-Farber Chief Medical Officer Craig Bunnell explains how a business background helps strengthen and inform his work in cancer care. 8 Bench to Bedside Massimo Loda, MD, PhD, and Mary Ellen Taplin, MD, pursue new treatments for prostate cancer. 31 Tech Preview: Mass Spectrometry Scientists use an advanced imaging system to aid research into brain tumors and drug delivery. 32 Why I Work Here Nutritionist Stacy Kennedy, MPH, RD, helps patients learn how to follow a healthy diet during treatment. 33 What I Know A father reflects on lessons learned from his young son’s journey back from a rare cancer. 34 Legislative Update 22 Young Lives on Hold Caring for young adults means treating their unique clinical and emotional needs. 26 Search for Shortcuts New medical tools may speed drug development and, in the process, offer better treatments for brain tumors. New oral chemo law benefits Massachusetts patients. 35 2012 Dana-Farber Annual Report 22 From the President Dear Readers, It has always been the hope of cancer patients that if no drug or other treatment can cure their disease, existing therapies can extend their lives long enough for scientists to develop new and better treatments. For too many patients, for too many years, that hope failed to materialize. Improved therapies didn’t arrive quickly enough to help patients in need of them. In recent years, however, as we’ve learned more about the basic biology of cancer and moved ever more agents into clinical testing, that pattern has begun to change. Increasingly, when a drug fails to work or loses its effectiveness after a period of months or years, there are new treatments available, often as part of a clinical trial. It is in this regard that cancer is gradually changing from an acute disease to a chronic one – one that can be lived with, and carefully managed, for the long term. There may be no one in medicine whose career better exemplifies this trend than Dana-Farber’s Ken Anderson, MD, PhD, profiled in this issue of Paths of Progress. Specializing in the bone marrow cancer multiple myeloma – and leader of a lab with a prodigious scientific output – Ken has often told patients that if they aren’t helped by a particular therapy, he’s working on new agents in the lab that may work better. His success has helped turn a disease that once was almost invariably fatal to one that is, for some patients, a chronic condition. Ken’s work is a model, and an inspiration, for researchers in many other types of cancer. One example is glioblastoma, a form of brain cancer which, as you’ll read in this issue, is a focus of intense effort at Dana-Farber to identify molecular targets for new therapies. The search for new treatments also motivates scientists’ efforts to distinguish “driver” genetic mutations, which propel the growth of cancer cells, from “passenger” mutations, which are bystanders to the cancer process – the subject of another article. Your interest in, and support of, our work at Dana-Farber is what makes these advances possible. I hope you find this issue of Paths of Progress enlightening and intriguing. Edward J. Benz Jr., MD President and CEO, Dana-Farber Cancer Institute 2 P at h s of Progress Spring/Summer 2013 www.dana-farber.org Around the Institute Red Sox and the Jimmy Fund Celebrate 60 Years Recipes and Photos for Your iPhone This year marks the 60th anniversary of the historic partnership between the Boston Red Sox and the Jimmy Fund, which supports adult and pediatric cancer care and research at Dana-Farber Cancer Institute. The milestone anniversary will be highlighted during the 2013 baseball season with activities and events, including the first annual Jimmy Fund Chorus and Jimmy Fund Month at Fenway Park in August. The Jimmy Fund Chorus will sing at select Jimmy Fund events throughout the year. This ensemble will include current and former patients and their family members, Dana-Farber staff, friends, and those who have been touched by cancer. This is a special way to celebrate the historic Red Sox-Jimmy Fund partnership. The celebration continues in August when Fenway Park celebrates Jimmy Fund Month. Events and activities will include the WEEI/NESN Jimmy Fund Radio-Telethon Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx held Aug. 27 and 28, featuring interviews with Dana-Farber patients, families, care providers, and scientists, as well as Red Sox manager John Farrell. Dana-Farber now offers two free apps for iPhones and iPads, one designed to help patients maintain a healthy diet and another aimed at showcasing photos that convey the spirit of Dana-Farber patients, staff, and volunteers. Ask the Nutritionist: Recipes for Fighting Cancer offers more than 100 healthy recipes, ranging from snacks to entrees and desserts. It also provides preparation directions, the ability to create a shopping list, nutrition tips, and nutritional information in a standard USDA label format. A diet section provides recipes with foods that are gluten-free or high-fiber, or provide immune support. Users can search recipes by symptoms commonly associated with cancer treatment, such as nausea or mouth sores, helping them customize a diet while going through treatment. The app also has tips for cancer survivors or anyone looking to make healthy food choices. New recipes are added each month. The photography app, Portraits of Care, captures glimpses of the cancer journey using images taken at DanaFarber designed to convey hope, inspiration, discovery, care, compassion, and collaboration. New images are added monthly. To download either app, search for “Dana-Farber” in the iTunes App Store. In the News Stuart H. Orkin, MD, chairman of the Department of Pediatric Oncology at Dana-Farber/Children’s Hospital Cancer Center, received the Jessie Stevenson Kovalenko Medal at the National Academy of Sciences’ 150th annual meeting in April. Jane deLima Thomas, MD, a palliative care physician and associate director of the Harvard Palliative Medicine Fellowship Program at Dana-Farber, was one of five U.S. physicians to receive the 2013 Hastings Center Cunniff-Dixon Physician Award. Dana-Farber researcher Kornelia Polyak, MD, PhD, was presented with the American Association for Cancer Research’s 2012 Outstanding Investigator Award for Breast Cancer Research at the San Antonio Breast Cancer Symposium. Spring/Summer 2013 P a t h s of Progress 3 A closer look at a few of the thousands of words associated with the complex fields of cancer medicine and research. androgen: A hormone, such as testosterone or androsterone, that controls the development and maintenance of masculine sex characteristics. atypical teratoid rhabdoid tumor (AT/RT): A rare, aggressive cancer that affects the kidney, liver, or central nervous system. It usually occurs in very young children. Ewing sarcoma: A relatively rare cancer that forms in bone or soft tissue, affecting mainly children and adolescents. Judy Garber, MD, MPH Garber Gets Nod from White House Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber/Brigham and Women’s Cancer Center, was recently appointed to the National Cancer Advisory Board by President Barack Obama. She will serve a six-year term on the 18-member committee, which advises the Department of Health and Human Services secretary and the National Cancer Institute (NCI). The committee reviews applications for grants and recommends approval of applications for projects that demonstrate potential for valuable contributions to cancer research and knowledge. In her work at Dana-Farber, Garber has helped develop national guidelines in genetics testing and medical oncology. Her research includes the study of breast cancer risk assessment, cancer genetics, and the treatment of triplenegative breast cancer. She served on the NCI’s Board of Scientific Counselors from 2007-2012 and she is the immediate past president of the American Association for Cancer Research. 4 P at h s of Progress Spring/Summer 2013 Lupron: Also known as leuprolide acetate, this drug is used primarily to treat advanced prostate cancer. The drug’s active ingredient (leuprolide) blocks the body’s production of the male hormone testosterone and the female hormone estradiol. metabolite: A substance created by or used for metabolism (when the body breaks down food, drugs or chemicals to create energy and the materials needed for growth, development, and reproduction). osteosarcoma: A bone cancer that most often affects the large bones of the arm or leg. It tends to occur in young people and affect more males than females. www.dana-farber.org CANCER DICTIONARY Around the Institute Around the Institute Cancer Death Rates Keep Dropping A recent report from the nation’s leading cancer organizations shows that death rates from all cancers for American men and women continued to decline between 2000 and 2009. The findings come from the latest Annual Report to the Nation on the Status of Cancer. Dana-Farber President and CEO Edward J. Benz Jr., MD, says that while improvements are needed, the results are encouraging. “People are surviving more and we are getting better at preventing some cancers,” said Benz. “But we’re not taking advantage of all the ways to detect cancers at an early stage when they can be the most curable.” The overall cancer incidence rate decreased for men and remained stable for women. While cancer incidence rates among children age 14 or younger increased slightly (0.6 percent each year from 1992 through 2009), overall death rates for cancer among children have steadily declined since at least 1975. Noting that there is plenty of work to be done to continue this trend, Benz said that the good news is that prevention strategies such as vaccinations for human papillomavirus (HPV) can have a big effect on incidence and death rates. “Many of the things that are still a problem in these statistics can be changed,” said Benz. Paths of Progress on Download our free app to read the latest cancer research and treatment advances on your tablet device (iPad or Android) or e-reader (such as a Kindle or Nook). The interactive edition of Paths of Progress includes all of the content from the print issue, along with digital-only extras, including photo galleries, videos, and more. An Immunology ‘Dream Team’ Dana-Farber researchers Glenn Dranoff, MD, Stephen Hodi, MD, and Kai Wucherpfennig, MD, PhD, were recently named recipients of a scientific “Dream Team” grant in cancer immunology from Stand Up to Cancer. The team, which includes scientists at eight cancer centers nationwide, will receive $10 million over three years to explore two therapies that harness the immune system to combat cancer. One focuses on a drug that may help heighten the response at immune checkpoint blockades – areas that maintain tight control over the body’s response to disease. The other involves transfusing disease-fighting T cells into patients with cancer. “The hope is to accelerate the development of new and more potent cancer immunotherapies by bringing investigators together through this Dream Team,” says Dranoff, leader of cancer immunology at Dana-Farber/Harvard Cancer Center. Your Tablet You can find the Paths of Progress app on the iTunes app store or visit the Android marketplace (search for “cancer research”). You can also find an e-reader version of the magazine in the Kindle and Nook stores. Links to the interactive versions, along with a downloadable PDF, are also available at www.dana-farber.org/ pathsofprogress. Spring/Summer 2013 P a t h s of Progress 5 Around the Institute A Milestone for Young Survivors Twenty years ago, the idea of cancer survivorship was in its infancy. Only a handful of programs offered expert follow-up care and wellness programs for patients who had completed treatment. One of the first of these groundbreaking programs opened at Dana-Farber in 1993 in the form of the David B. Perini Jr. Quality of Life Clinic, the pediatric survivorship program at DanaFarber/Children’s Hospital Cancer Center (DF/CHCC). “Survivorship rates were starting to rise and we were just beginning to understand the specific long-term issues that our young survivors faced,” says Holcombe Grier, MD, professor of pediatrics at DF/CHCC, who served as co-director of the Perini Clinic in 1993. “We saw that we needed a more controlled, unified way to address specific long-term issues.” Today, an estimated 13.7 million Americans are cancer survivors, and the demand for survivorship services is on the rise. Programs like those offered through the Perini Clinic and Dana-Farber’s Adult Survivorship Program give patients access to a range of experts, from psychologists to fertility and cardiac care experts, who help address post-cancer challenges and concerns. They provide childhood and adolescent cancer survivors access to the expertise, education, and support needed to manage key survivorship issues, including the long-term adverse effects of treatment, the risk of second cancers, and social and psychological concerns. Such services are an integral part of care at comprehensive cancer centers like Dana-Farber, and they have become an expectation for most patients today. “It’s remarkable to see how the conversation has changed,” Grier says. “When I sit down with families and talk with them about a child’s new cancer diagnosis, it’s no longer just about treatment. While much of the conversation is ‘will my child survive?’, an almost equal amount is on ‘how will this affect my child over the long term?’” To learn more, visit www.dana-farber.org/perini-clinic. Connect with Dana-Farber Online Whether it’s through Facebook, YouTube, or Twitter, connecting with Dana-Farber online has never been easier. You’ll find our “Insight” blog at www.blog.dana-farber.org/insight, or keep in touch through your favorite social networking sites, such as Google+, Pinterest, or YouTube. Visit us online at www.dana-farber.org/socialmedia to find links to all of our social media sites, then follow us to keep up with the Institute’s latest news and research, while showing your support for vital research and patient care. 6 P at h s of Progress Spring/Summer 2013 BY THE NUMBERS 19,614 Combined number of hours donated last year by Dana-Farber volunteers 721 Number of clinical trials open to Dana-Farber patients in 2012 42 feet Length of new Blood Mobile introduced in 2013 and made possible by the Friends of Dana-Farber and Friends of Brigham and Women’s Hospital More than 3,000 Number of tumor samples now classified in Profile, an ambitious effort by Dana-Farber and Brigham and Women’s Hospital to scan tumor samples from all adult consenting patients and identify the sets of DNA mutations – or genotypes – that drive tumor growth $72,000 Amount donated by DanaFarber staff to patients and families participating in the Institute’s Seasonal Giving Program, a program to help ease the financial burden of a cancer diagnosis 242 Registered nurses who staff inpatient units at Dana-Farber/Brigham and Women’s Cancer Center 5,234 Number of bicyclists who participated in the 2012 Pan-Massachusetts Challenge (PMC), which raised more than $37 million for the Jimmy Fund. The event attracted cyclists from nine countries and 36 states. www.dana-farber.org Six Questions For ... Interview by Christine Cleary Craig Bunnell, MD, MPH, MBA “I love my job,” says Craig Bunnell, MD, MPH, MBA, Dana-Farber’s Chief Medical Officer (CMO) since July 2012. Bunnell, a medical oncologist and a former clinical director of the Breast Oncology Center, has been a faculty member at Dana-Farber/Brigham and Women’s Cancer Center since 1997. He is leading a major initiative aimed at making the experience of patients smoother and more efficient. Bunnell explains how his background in medicine, public health, and business prepared him for this role. Q: What does the CMO job entail? A: My charge is to make sure we deliver high-quality, cost-effective, efficient, and patient-centered care. I engage physicians and collaborate with other departments such as Nursing, Human Resources, and Finance – as well as our satellite centers and partner institutions – to see that we meet our research and clinical care goals. Q: How does your role support Dana-Farber’s goals, particularly those aimed at quality improvement? A: Quality improvement is a responsibility shared by all of us, and it affects every aspect of the work I do. Patients come here with the belief that they will have a quality experience. They expect their care at Dana-Farber to be better than what they would find elsewhere. We have to deliver on this. Q: Describe your vision for effective patient care. A: This vision is for the best possible care to be given by the right professional at the right time for the patient. For example, if administrative work is handled by an administrative expert, then the program nurse is freed up to do clinical work, which in turn frees up the physician assistants, nurse practitioners, and physicians. Each person is doing what he or she does best, and this way of working is standardized across the Institute. In the end, the patient has a better experience. Q: How do you work with patients to make improvements in care? A: At Dana-Farber, patients are an inte- gral part of the way we make changes. They are involved, as volunteers, on every committee. We also receive their feedback through surveys and other means. Even complaints are a way to learn. I write back to patients all the time, and I thank them for pointing out an opportunity for us to improve. Q: You have several degrees. How did these areas of study prepare you for your job? A: I pursued an MPH [master’s degree in public health] while in medical school because I was interested in health policy and clinical research design. Later on, when I became clinical director for breast oncology here, I discovered how much I liked organizational operations, so I went to business school and it really energized me. Now I know how much we can learn from other industries. Xxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxx xxxxx Q: Do you still take care of patients? A: Yes, I see breast cancer patients two days a week. I love being a doctor, and I consider patient care a critical part of my role as CMO. This keeps me close to the patient experience. I only ask other clinicians to do what I am willing to do myself. Spring/Summer 2013 P a t h s of Progress 7 Bench to Bedside by ROBERT LEVY R esearcher P rofile A thletes caught using performance-enhancing drugs are betrayed by their own blood, which carries chemical evidence of substances they’ve ingested or injected. That evidence isn’t the drug itself, but bits and pieces of it that have been split off and reassembled by the body in a process known as metabolism. At Dana-Farber, Massimo “Max” Loda, MD, and his colleagues are conducting equivalent exams on prostate cancer cells, trying to discover how metabolism differs in tumor cells and normal cells, and what those differences Massimo Loda, MD, PhD 8 P at h s of Progress can tell scientists about genes behind the disease. “Metabolism is the process by which cells and tissues break down nutrients and use them to grow, reproduce, and perform their function within the body,” says Loda. “My lab uses metabolism as a window into the genes that cause and drive prostate cancer.” His focus on metabolism was inspired by a discovery about an enzyme, a protein that speeds chemical reactions in the cell. Half a dozen years ago, he and his associates found that a long-overlooked enzyme known as fatty acid synthase, or FAS, is essential for prostate cancer cell survival. Blocking the enzyme in laboratory cultures of prostate cancer cells caused the cells to die. As an enzyme, FAS is deeply involved in cell metabolism. “The discovery of FAS’s role in prostate cancer led us to the broader field of metabolic pathways – the chain of events by which compounds are modified to produce other products within the cell,” Loda says. His team began making “metabolic “We can see which profiles” of normal and cancerous prostate cells, identifying the metabolic pathways molecules created as metabolism are altered in prosproceeds and the levels at which tate cancer cells they’re produced. and which are not.” “We focus on the molecules – or metabolites – that result from enzymes’ action within cells,” Loda explains. He and his associates found stark differences in the metabolic profiles of normal prostate cells and prostate cancer cells – differences that may hold clues to better treatments. “We can see which metabolic pathways are altered in prostate cancer cells and which are not,” Loda explains. “We apply that information to what we’ve learned from genomic research into the disease. We know, for example, that prostate tumors driven by certain mutated genes have distinct metabolic profiles. By combining the two approaches, we hone in not only on cancer-causing genes, but also on the metabolic pathways they change. Both the genes and pathways can be targets for new therapies.” Loda’s research has also shown that metabolic profiles can vary from one prostate tumor to another. Those differences may serve as biomarkers, indicating which prostate cancers are likely to respond to certain drugs, and which are not. Spring/Summer 2013 www.dana-farber.org Bench to Bedside by ROBERT LEVY C linician P rofile I magine trying to extinguish a fire that burns even after its oxygen supply has been cut off – a blaze with the ability to produce its own oxygen. For doctors and patients who battle aggressive prostate cancer, the predicament is much the same. Prostate tumors fuel their growth with the male hormone androgen, which is produced in the testes, the adrenal glands, and – most troublesomely – in the cancer cells themselves. Drugs that shut down production of androgen in the testes and adrenal glands can bring tumor growth to a halt. But without a way to stop tumors from making homegrown androgen, such remissions rarely last long. Mary Ellen Taplin, MD, has spent more than 20 years working to improve the options for men with prostate cancer treated at Dana-Farber/Brigham and Women’s Cancer Center. Last year, she and her colleagues scored a major success with a clinical trial of a drug that ranges far and wide to stifle androgen production in the body. The trial involved 58 men “This is the first trial with aggressive prostate cancer tumors likely to ever to show that spread beyond the prostate treating high-risk gland. “Such tumors are prostate cancer rarely cured by surgical repatients ... can moval of the prostate gland alone,” Taplin says. “Therahave such a powerful pies that combine surgery clinical result.” with older, androgen-blocking drugs haven’t had much of a positive impact on those results. Research indicated a broader-acting anti-androgen agent might be more effective.” Half of the trial participants received the standard hormone-blocking drug Lupron, and half received Lupron and the study drug abiraterone acetate, which handcuffs androgen production in the tumor as well as in the testes and adrenal glands. After three months, all participants began receiving the two-drug combination. Three months later, all the men’s prostate glands were surgically removed. Pathology exams showed that 34 percent of the participants had no or almost no tumor tissue left – a vast improvement over conventional hormonal therapy. “This is the first trial to show that treating high-risk prostate cancer patients with neo-adjuvant therapy [in which participants receive hormone or chemotherapy prior to surgery] can have such a powerful clinical result,” Taplin says. The next step will examine which dose and combination of androgen-blockers has the best result. The study results are, in a way, a vindication of the promise that Taplin saw in prostate cancer research when she entered the field in the early 1990s. “At the time, much less was known about the role of the androgen receptor [a protein on cells that switches their growth on and off] in prostate cancer than about the role of estrogen receptor in breast cancer,” she observes. Mary Ellen Taplin, MD Spring/Summer 2013 P a t h s of Progress 9 Photo Illustration by Jessica Walker 10 P at h s of Progress Spring/Summer 2013 www.dana-farber.org Trouble Makers by Robert Levy picking out the genes that cause cancer Spring/Summer 2013 P a t h s of Progress 11 TCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATC CGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGAT GATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGA ATCGTCGATCGATCGTCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCGATCG N ot long ago, the task of linking a mutated gene to cancer could consume the better part of a scientist’s career. Today, it may take as long as a week. Advanced DNA-sequencing technology can speedily deliver lists of the mutations within a set of tumor cells – the various misspellings, duplications, and garblings of the genetic code that can send cell growth into overdrive. And impressive lists they can be. If the cancer being scanned is a lymphoma or leukemia, the number of muta- 12 tions may be less than a dozen. If it’s a lung cancer or melanoma, the figure is apt to be in the hundreds, if not thousands. The challenge for scientists, then, has shifted from one of scarcity to surplus. In tumor cells with, say, 1,000 mutations, the number of mutations actually driving the cells’ growth and survival may be relatively small (though no one knows how small). The remainder of the mutations, regardless of where or why they arose, have little influence on the tumor’s behavior and are, essentially, along for the ride – hence their name, “passenger” mutations. When designing new cancer drugs, investigators clearly want to aim at the mutations responsible for cancer cells’ chaotic growth. The question then becomes how to distinguish drivers from passengers, the legitimate targets from the decoys. The mutations themselves offer few clues: a typo in a single letter of DNA can sometimes wreak havoc; a gene copied multiple times over may have no negative impact. “For lung cancer and many other cancers, we’re drinking from a firehose, trying to select out the few gene mutations that matter amid the torrent of mutations that are less critical,” says Kwok-Kin Wong, MD, PhD, scientific co-director of the Belfer Institute for Applied Cancer Science at Dana-Farber, which seeks to discover new treatments by understanding the mutations that make cancer go. The Likeliest Suspects Getting a bead on driver mutations wasn’t difficult initially. “There are a number of mutated genes that have been known for 20-25 years to be involved in cancer – genes such as ras, BCR/ABL, and Myc,” says William Hahn, MD, PhD, Dana-Farber’s deputy scientific director and director of the Institute’s Center for Cancer Genome Discovery. “The problem was that, other Of the many gene mutations within a cancer cell, only a relatively small number may be driving the cancer. P at h s of Progress Spring/Summer 2013 CTCA GATC- For Belfer Institute leaders (from left) Jesse English, PhD, Pasi Jänne, MD, PhD, and Kwok-Kin Wong, MD, PhD, studying cancer’s environment within the body is key to understanding the disease. than these, we knew very little about which genes underlie different types of cancer.” Researchers began by focusing on the mutations most clearly connected to cancer. Scientists knew that enzymes known as kinases are often abnormal in cancer cells. So it was natural for kinase genes to be among the first considered as drivers. Another clue was how often a particular gene is found to be mutated in cancer. “If it happens at a highenough frequency – if it occurs in, say, 30 percent of cancers of a certain type – we’ll be pretty suspi- cious that it plays an important role,” Hahn remarks. “Researchers initially looked at the genes that had been extensively studied and described,” Wong says. “From that base of knowledge, you start building a picture of how they contribute to cancer. If you’re interested in a gene about which little is known, you have to build that biological understanding yourself. That is what the Belfer Institute and other labs at Dana-Farber are doing.” The challenge of identifying the drivers goes beyond finding which mutations are troublemakers in Spring/Summer 2013 P at h s laboratory specimens of cancer cells. Tumors are best understood within their natural surroundings, the layers of normal and near-normal tissue that enfold them within the body. A group of gene mutations that causes cell reproduction to go berserk in petri dishes may have an entirely different effect – or no effect – in actual organs and tissues. Laboratory techniques that simulate the living environment of tumors are critical to this research. “When we look for driver mutations, we need to take into account all the different types of cells that are of Progress 13 Genome Research ‘Goes Viral’ Investigators in Dana-Farber’s Center for Cancer Systems Biology (CCSB) have taken a novel approach to distinguish driver from passenger mutations. The key to their technique: viruses, the primal perpetrators of cellular havoc. After a virus infects a cell, proteins made from the virus’s genes begin interacting with the cell’s own proteins. These interactions can interfere with the cell’s normal functioning and the activity of its genes – so recklessly, sometimes, that the cell becomes cancerous. The disruptions produced by cancer-causing viruses often mimic those triggered by gene mutations. “That led us to ask, ‘What if we systematically examine the interactions between normal cell proteins and the proteins made from cancer cell viruses?’” says Michael Cusick, PhD, of the CCSB, who helped lead the research. “Because viral proteins and gene mutations cause cancer by similar mechanisms, could we use the viral proteins as stand-ins for identifying proteins – and the underlying gene mutations – associated with cancer?” To find out, researchers from the United States and Canada collected 144 proteins from four viruses linked to cancer and screened them one by one against 20,000 different proteins in human cells, recording which ones interacted. The end tally was the identification of roughly 950 viral targets, cell proteins potentially associated with cancer. around the tumor, that feed the tumor and promote its growth,” says Jesse English, PhD, the Belfer Institute’s head of research. “We’ve developed several strategies for studying the effect of mutations within the context of a tumor’s normal environment.” Diving In Belfer Institute researchers use two main approaches – or platforms – to cull driver mutations from the throng of passengers. The first is contextspecific screening (CSS). English explains: “In any given tumor type, there are often baseline mutations – a small group of mutations that don’t necessarily make a cell cancerous, 14 P at h s of “Viruses have spent millions of years perfecting the art of interacting with cells – of taking advantage of gene pathways that are essential for the cell and may therefore be essential to cancer,” Cusick remarks. “We’re now using them as a guide to the mutations that are most important in cancer.” –RL Electron micrograph of a negatively stained human papilloma virus (HPV) that occurs in human warts. Warts on the hands and feet have never been known to progress to cancer. However, after many years, cervical warts can become cancerous. but start it in that direction. The question is, which additional mutations will push the cell over the edge into cancer?” Belfer Institute scientists have created such almost-cancer cells for a variety of tumor types. They slip suspected driver mutations into the cells’ DNA and implant the cells in lab animals, in the same tissue where such cells might naturally be found. If the cells become cancerous, it’s an indication that the added mutations are indeed drivers. The second strategy is a “depletion screen” involving shRNA (the “sh” stands for “short hairpin” but might just as well stand for “Shhh!” as the Progress Spring/Summer 2013 technique involves silencing genes one at a time). “We use viruses to carry shRNA into laboratory samples of tumor cells,” explains Belfer Institute scientist Mark Bittinger. “The RNA shuts down a specific gene, and we track whether the cells stop growing and die. It’s a systematic way of determining whether a particular gene is necessary for tumor cell survival and proliferation. “This approach, known as RNA interference, mimics the way a drug against an individual gene would work. It has become the workhorse of efforts to discover cancer-related genes that make good targets for new therapies.” www.dana-farber.org Hahn and his colleagues have harnessed RNA interference in an effort dubbed Project Achilles. Named after the mythical Trojan War hero who was killed by a wound to the weak spot in his heel, the project is concerned with vulnerabilities, specifically the genes on which cancer cells depend for their growth and survival. “We’re screening at least 500 cancer cells lines in which we know all of the genetic alterations and asking, if we turn off those genes one by one, can we identify which are critical? It’s our hope that the project will result in a global picture of how to find those vulnerabilities,” Hahn comments. “We’re about halfway through the project [which began in 2010], but it’s already enabled us to begin exploring the links between certain mutations and cell survival.” Hahn and other scientists emphasize that no single approach – whether in laboratory cell cultures, tumor tissue samples, or animal studies – will be sufficient to decisively label a particular gene mutation as a driver. Rather, it will require a combination of these approaches to identify the most likely offenders. Also, driver mutations rarely work solo. In the vast majority of cancers, it isn’t one mutation but a combination of them that are responsible for turning a cell cancerous and keeping it that way. Researchers are hard at work trying to determine which combination of mutations provides the formula for cancer, and which combination of therapies can undo the damage those mutations have produced. William Hahn, MD, PhD (right), with Rameen Beroukhim, MD, PhD, leads Project Achilles, named for the mythical warrior with a single vulnerability. Spring/Summer 2013 P at h s of Progress 15 Man Mission on a 16 P at h s of Progress Spring/Summer 2013 www.dana-farber.org Ken Anderson: Changing the Natural History of Multiple Myeloma by Elizabeth Dougherty A mong the many photographs lining the shelves in his office, Ken Anderson, MD, is quick to point out one. In it, he stands with Robert Kraft, owner of the New England Patriots and patron and co-founder, with Anderson, of the Kraft Family Blood Donor Center at Dana-Farber Cancer Institute and Brigham and Women’s Hospital. The two are smiling as Anderson holds up a 2004 Super Bowl ring. Anderson, who is director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber/Brigham and Women’s Cancer Center, says he counts Kraft as a “friend for life, both personally and professionally.” Anderson, the Kraft Family Professor of Medicine at Harvard Medical School, and Kraft have been close friends for 30 years. Anderson says it’s relationships like these – with colleagues and collaborators, trainees, and, most important, with patients and families he has cared for – that are the secret to his success. In his four decades of practice and research, including 32 years at Dana-Farber, Anderson has played a central role in transforming myeloma, a cancer of the bone marrow, from a near immediate death sentence to, in many cases, a chronic, manageable illness. From the 1970s through the ‘90s, not a single new myeloma drug made it into clinical practice. But during the last decade, Anderson, a slight man with kindly eyes and a ready smile, helped shepherd multiple new drugs from laboratory bench through regulatory approval and to the patient bedside. “Partnership is absolutely key,” says Anderson, who received a 2012 Medal of Honor in Science from the American Cancer Society for bringing his research into the clinic. “We practice team science. We work with industry, regulatory authorities, and funding agencies. But most important, our patients are the heroes, inspiration, and reason for all we do.” Spring/Summer 2013 P a t h s of Progress 17 Anderson arrived at Johns Hopkins University in 1973 for medical school, inspired by his mother, a nurse, to become a small-town general practitioner. He also had a keen interest in science. In his mind, however, blending science and the practice of medicine as he conceived it – “on the front lines, taking care of people in the community” – wasn’t in the realm of possibility. Then he met Richard Humphrey, a multiple myeloma doctor who was growing myeloma tumor cells in the laboratory and testing them against conventional drugs. Humphrey introduced Anderson to clinical research, and also taught him the meaning of success: Make science count for patients, and treat patients as family. So imbued is Anderson with these two principles that he has, by word and example, passed them on to those he mentors. “He always told me, as long as you keep the patient in mind, bone marrow aspirations, they also grow readily in the laboratory, making it possible to model the disease and put science to work against it. The stage was set. Anderson began pursuing myeloma research immediately. Making Science Count Anderson attributes many of his subsequent discoveries to simply following science trends. “In the ‘80s, it was a Golden Age of monoclonal antibodies,” he says, his eyes sparkling as he recalls treatment advancements that came from this work. Monoclonal antibodies grab onto invaders such as viruses and cancer cells and allow the immune system to attack. Anderson used antibodies that target myeloma tumor cells to improve the success of bone marrow transplants when patients self-donate marrow. Even after chemotherapy, such marrow still contains some malignant “I have been blessed to have colleagues here and around the world passionately committed to curing myeloma ...” – Kenneth Anderson, MD you’ll never go wrong,” says Noopur Raje, MD, who trained in Anderson’s lab a decade ago and now leads her own myeloma lab and practice. In the early 1970s, there were very few people working on myeloma and survival was measured in months. “There was a glaring and urgent need to make things better for patients,” says Anderson. Research into myeloma was also primed for improvement. Not only are myeloma tumor cells relatively easy to gather from patients, through 18 P at h s of cells. Anderson found that treating it with antibodies helps clear the tumor cells and delays relapse. Later, Anderson worked to transform bone marrow transplants into stem cell transplants. The method involves harvesting and reintroducing a patient’s own blood stem cells to regenerate the blood and immune system after high-dose chemotherapy. Again, this improved survival. As science began to uncover the importance of cytokines – proteins that cue cells to grow and influence Progress Spring/Summer 2013 their behavior – Anderson’s research expanded in that direction. This led to a better understanding of the cellular circuitry that drives myeloma. In the mid-1990s, Anderson discovered that a switch inside myeloma cells, NF-kB, was important to myeloma cell growth and survival, making it a promising drug target. At about the same time, colleagues at Harvard Medical School were working on a new drug, an inhibitor that blocks the proteasome, the cell’s garbage collector. That drug, it turned out, worked by inhibiting NF-kB, Anderson’s prime target. Further research in Anderson’s lab confirmed the effectiveness of the drug against myeloma. Then, in a phase 1 clinical trial, a myeloma patient had a complete response. All signs of the disease vanished. Just three years later, in 2003, the FDA approved the drug, called Velcade, which today is standard treatment for newly diagnosed myeloma. “It went from the bench to the bedside very quickly,” says Anderson, who with his colleagues won the prestigious Warren Alpert Foundation Prize at Harvard Medical School for this work in 2012. “The whole concept of benchto-bedside-and-back research was really new,” says Faith Davies, MD, who joined Anderson’s lab in 1999 for a three-year fellowship. She is now a myeloma investigator at the Institute of Cancer Research in London. “Others may have been doing it, but Ken really drove it.” Around the same time, Anderson was investigating thalidomide, another promising myeloma drug. He modeled not just patient tumor cells but also, as he says, “the neighborhood” of the tumor, including non- www.dana-farber.org cancerous immune and other cells. The tumor’s neighborhood – or “microenvironment” – mattered in myeloma treatment because myeloma cells that adhere to the microenvironment don’t respond to conventional chemotherapy drugs. These more life-like models allowed Anderson to discover that thalidomide and its close cousin lenalidomide (brand name Revlimid) work as immunomodulators, drugs that recruit immune cells to fight cancer. Paul Richardson, MD, his colleague and clinical director of the Lipper Center, led the first human trials, setting the stage for the 2006 approval of lenalidomide to treat myeloma. Modeling the microenvironment has since proven to be a valuable tool in translational research. “Ken’s work has shown that when drugs work in laboratory models of the tumor that include the context of the microenvironment, they tend to work better in patients,” says Raje, who, along with Davies, collaborated on these findings. Myeloma Mixology Researchers now know that cancer is heterogeneous (many genetic mutations drive a single tumor) and must be treated with combinations of therapies that target different drivers. In some forms, such as testicular cancer and certain types of leukemia and lymphoma, such drug cocktails have led to cures. So Anderson is looking for synergistic combinations of drugs and therapies for myeloma. Synergy can happen if, for example, one drug undoes the mechanisms that cause resistance to another drug. He also hopes to personalize treat- Kenneth Anderson, MD (right), has had a lifelong friendship with New England Patriots owner Robert Kraft (left), a passionate supporter of the fight against cancer. ment by categorizing patients based on the molecular pathways that are driving their cancer, as determined by tumor genomics, and to prescribe combinations of drugs based on those categories. “The more we understand, the more we realize how complicated this disease is,” says Anderson, who, along with colleague Nikhil Munshi, MD, is finding that myeloma tumors have many mutations even at the very start of the disease. “Hardly ever will it be enough to use just one targeted agent.” One combination, Velcade, Revlimid and Dexamethasone, shows promise in all patients, with all signs of myeloma vanishing in half. Given these unprecedented results, Munshi, Richardson, and Anderson have launched a trial to test this combination in newly diagnosed myeloma patients. Half of the participants will receive stem cell transplants, testing whether the combination increases transplant success, and vice versa. “My prediction is that science will inform the design of four- or even five-agent treatment combinations Spring/Summer 2013 P a t h s that will markedly improve outcomes and lead to potential cures,” he says. Anderson’s influence is behind much of the progress made in myeloma over the past four decades. Yet Anderson deftly passes the credit. “I have been blessed to have colleagues here and around the world passionately committed to curing myeloma, and courageous patients who are a daily source of inspiration.” “He’s so humble about his achievements,” says Raje, who still attends Anderson’s weekly lab meetings and calls him regularly for input. When Anderson looks back on his 40-year journey, he shakes his head in disbelief. “What a privilege it has been for me to watch the natural history of myeloma change, see trainees become leaders, and watch patients share the joys of life with their families. It doesn’t get any better than this!,” he says. Nevertheless, when he looks ahead, he has the energy of a man just about to begin. See Dr. Anderson explain multiple myeloma. Visit www.bit.ly/Z1WtwX. of Progress 19 SCIENCE ILLUSTRATED Cancer Cell with BRCA1 or BRCA2 Mutation by Robert Levy Illustration by Jessica Walker and john digianni PARP T he renegade behavior of cancer cells results from mutations or abnormalities in key sets of genes. As scientists have come to realize, these same mutations can leave the cells vulnerable to cleverly-designed therapies. One example involves a treatment for breast and ovarian cancer patients who have inherited mutations in the genes BRCA1 or BRCA2. As depicted here, the approach turns these otherwise dangerous changes to patients’ advantage. 1) Everyday wear and tear or environmental hazards can damage cells, often producing a break in a single strand of DNA. Normally, a protein known as PARP helps fix such single-strand breaks. 2) Treating such patients with PARP-blocking drugs can prevent such breaks from being repaired in cancer cells. DNA Break 1. Single Strand DNA Break 3) With PARP sidelined, DNA damage accumulates, eventually producing breaks in both strands of the molecule. In most people, the BRCA genes handle two-strand repair jobs, but patients who inherit BRCA1 or 2 mutations have only one functioning copy of these genes, rather than the usual two. In such patients’ tumor cells, even that one good copy is lost. The result: mounting, irreversible DNA damage to tumor cells. 4) Its DNA irreparably broken, the tumor cell can no longer sustain itself and dies. 20 P at h s of Progress Spring/Summer 2013 www.dana-farber.org Outmaneuvering Cancer 3. Double Strand DNA Break PARP 2. Treatment with PARP Inhibitor PARP BRCA DNA Break PARP Inhibitor DNA Break BRCA PARP Inhibitor 4. Dead Cancer Cell Spring/Summer 2013 P at h s of Progress 21 Young Lives ON HOLD Caring for young adults means treating their unique clinical and emotional needs Rebecca Blumenfeld always planned on getting married and starting a family. She just didn’t expect she would need to do both so suddenly. In the fall of 2011, Blumenfeld was newly engaged and attending graduate school just outside Boston. When a small bump on her leg rapidly grew in size, a succession of doctor visits ended with surgery to remove a tumor and, then, a diagnosis of a rare form of osteosarcoma – bone cancer. Suddenly, at age 29, Blumenfeld felt like the life she’d mapped out was contracting quickly. Instead of graduate school and wedding plans, she was faced with a second, more invasive surgery and a year of chemotherapy. She and her fiancé, Jeff, immediately obtained a marriage license, found a justice of the peace, and spent their first week as husband and wife undergoing in vitro fertilization and harvesting embryos in case Blumenfeld’s treatment caused fertility problems. Then, in the second week of married life, came chemo. Young adult patients have long been cancer’s forgotten group. Children, despite making up just 2 percent of all cancer cases, get a disproportionate share of research funding, clinical focus, and media attention. Middle-aged and older patients are the primary beneficiaries of clinical trials, research protocols, and support groups. For those caught in between, things can be confusing. Too old for the pediatric clinic and its playroom, too young to feel comfortable in an adult clinic alongside people their parents’ age, young adults facing cancer often feel isolated. Just about 10 percent of outpatients at Dana-Farber/Brigham and Women’s Cancer by Saul Wisnia 22 P at h s of Progress Spring/Summer 2013 www.dana-farber.org Left to right: Divya Raju, Rebecca Blumenfeld, and Ben O’Clair were all forced to halt major life events during cancer treatment at Dana-Farber. Spring/Summer 2013 P at h s of Progress 23 Center (DF/BWCC) are between ages 18 and 35. Peers don’t understand what they are going through, and sometimes their own families are not sure how to help. Major milestones, such as going to college or beginning a career or family, are often disrupted. DF/BWCC’s Young Adult Program is designed to help these patients find their place and each other. It offers individual and group counseling, educational events, and peer support through face-to-face meetings and a secure website with online forums and information. “Young adults can be taken off track by cancer, and it’s hard for them to transition back into regular life, for practical and existential reasons,” says Karen Fasciano, PsyD, a clinical psychologist and director of the Young Adult Program. “Their peer group hasn’t experienced this, and their perspective on life and what they value may change.” Blumenfeld says she suppressed her emotions for the year she was in active treatment, only to have them come flooding back after her PortA-Cath device was removed last December – exactly one year after her first chemotherapy infusion. “During treatment, I was concretely connected with the physical – and my body and pain and nausea and discomfort – that I didn’t have time to feel anything,” says Blumenfeld, who was a “very part-time” student during this period. “Since treatment, I’ve been reflecting. I’m angry and frustrated that this was not the year it was supposed to be. I had to put off finishing school, my relationship was constantly challenged, and I don’t feel like my body belongs to me anymore.” Blumenfeld credits the Young 24 P at h s of Recent findings show that many young adult patients may respond best to a chemotherapy regimen designed for children. Adult Program with helping her through. After attending DF/BWCC’s annual young adult conference, she was “amazed” to meet so many patients her age. She also met regularly with Fasciano, with whom she discussed her relationship with both her husband and her parents – on whom this fiercely independent woman had to become largely dependent. Ben O’Clair faced several similar obstacles. He was a 21-year-old college senior taking final exams when he learned he had Ewing sarcoma – another form of bone cancer – and had to leave school immediately. “I had just gotten to the point where I was preparing for graduation and interviewing for jobs and internships,” recalls O’Clair, now 24. “I had to stop and put it all on hold.” Today O’Clair serves on the Young Adult Program advisory committee. “We’re giving people a chance to get the support they need and connect with others are out there,” he explains. “I’m working on the website; my favorite feature is a chat room where people can arrange to meet up with fellow patients.” ‘Awakening’ Research Changes in how young adults are treated at DF/BWCC are not limited to their unique emotional concerns. There is an increased focus on the clinical and scientific differences that can arise in tumors found in this age population, and on tailoring treatments to best address them. Stephen E. Sallan, MD, chief of staff emeritus and a pediatric Progress Spring/Summer 2013 oncologist at Dana-Farber/Children’s Hospital Cancer Center, says there are several key obstacles in identifying and treating young adults. “These are among the most uninsured and unemployed individuals in the country, so they are often not being seen regularly by a physician,” says Sallan. “They feel they are immortal and can’t get sick, so they may initially ignore their symptoms. Many times we don’t get to them until they show up in an emergency room, with or without their parents.” Sallan says that it has long been known that some cancers – sarcomas, lymphomas, leukemias, some brain tumors, and some germ cell cancers – appear more often in young adults. Researchers recently found that a significant portion of these patients may respond best if given a chemo regimen designed for children. Acute lymphoblastic leukemia (ALL), the most common childhood cancer, has a survival rate of 85 percent or higher when treated in patients age 15 and under. This rate was always worse in young adults until a pair of oncologists at the University of Chicago – Wendy Stock, MD, and Jim Nachman, MD – found that putting patients ages 18-30 on a pediatric chemotherapy protocol led to much better outcomes. “When I first heard their talk, it awakened me,” says Sallan. In 2000, along with three other cancer centers, Dana-Farber began treating young adult ALL patients with pediatric protocols. Survival rates went from 40 percent to 70 percent. www.dana-farber.org Researcher Katherine Helming (left) has seen cancer from both sides; Stephen Sallan, MD, has sought cures for her and others for 40 years. Back to Life The key now, Sallan and others agree, is to increase the number of young adults on clinical trials for all cancers so that physician-scientists can learn more about what makes their tumors respond differently. “We want to develop clinical trials geared to the physiological and biological needs of this group,” says Suzanne George, MD, clinical director of the Center for Sarcoma and Bone Oncology at DF/BWCC. “If you look at sarcoma outcomes by age subtypes, which typically occur in the young adult population, patients over 18 typically do worse than younger patients, and yet are treated on the same protocol. There is an opportunity to better understand the disease biology.” Adds Sallan: “Diseases are sometimes identical regardless of age, and sometimes are not. We are learning the importance of recognizing these similarities and differences. Some of the difficult therapies and their side effects that can be tolerated by children occasionally prove to be too toxic for those in their 20s and 30s.” Katherine Helming has an innate understanding of this situation. At age 23, while a Harvard Medical School doctoral student training in a cancer biology lab at Dana-Farber, she was diagnosed with leukemia. Like O’Clair, she had to take a full year off from her studies and, due to intensive chemotherapy treatments, spent many weeks of 2011 as an inpatient at Brigham and Women’s Hospital or in isolation to prevent infection. Nurses told Helming she had to “stop being a scientist worrying about what was going on with my cells, and start being a patient.” Easier said than done, until she joined the Young Adult Program. “The most important thing the program did was connect me with other young adults in my situation,” Helming says. “If we didn’t have the same type of cancer or weren’t in the same treatment stage, we still had a lot in common – relating to our peers, becoming dependent again on our parents, and navigating the return to school or work.” Helming had a difficult time Spring/Summer 2013 P at h s returning to her doctoral program during her second year of treatment. From the windows in Dana-Farber’s Louis B. Mayer Research Laboratories, she could look across the street into the Yawkey Center for Cancer Care, where she was still receiving once-weekly chemotherapy. “Sometimes that was too overwhelming to get my head around,” Helming admits. “I got tired very easily and I didn’t want to push myself too hard in the lab, but I still wanted to contribute.” Even after treatment, young adult patients like Helming face emotional challenges. They’re often expected to bounce right back to their old lives. “People will say to them, ‘Aren’t you lucky your cancer is gone?’ at the same time they might really be struggling,” says Ann LaCasce, MD, a hematologic oncologist and director of Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program. “They don’t have the support they need, and every time something happens to them medically, they’ll be certain their disease is back – even if it isn’t.” Now these patients have that support. Whether or not their cancer returns, they are better equipped to deal with it from an emotional and physical standpoint. For Rebecca Blumenfeld, that means joking about her “real first year of marriage” as she prepares for a larger ceremony at a botanical garden in June. Watch a video about young adult patients. Visit www.bit.ly/12Tq0S2. of Progress 25 26 P at h s of Progress Spring/Summer 2013 www.dana-farber.org The search for shortcuts New medical tools may offer better predictions and drug treatments for brain tumors by richard saltus C linicians and researchers in neuro-oncology at Dana-Farber are excited. Experts have spent decades trying to find ways of controlling or killing glioblastomas, the most highly malignant of brain tumors, but progress has been slow. Now, scientists are discovering a growing list of molecular targets for “smart” drugs that might dent the tumors’ resistance that has stymied conventional therapies, and could potentially lengthen survival and improve quality of life. Until glioblastomas yield to some future breakthrough, the best near-term bet for helping patients is to develop and test these targeted drugs – first one-at-a-time, then in combinations – say the researchers. Rather than aiming to destroy tumor cells by blasting them with radiation and DNA-damaging chemotherapy, the new agents are designed to block runaway growth signals that drive the tumors’ aggressive spread. “There is hope that over the next few years, new cocktails of drugs will be available to target the key molecular pathways involved in these tumors,” says Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber/ Brigham and Women’s Cancer Center (DF/BWCC). However, the road from promising candidate to effective treatment is often fraught with detours and delays. Each new compound from pharmaceutical laboratories comes with a list of necessary questions: Can it reach its target within the brain? Will it be effective in disrupting tumor growth? Does it have acceptable risks of side effects? Every new agent must pass these tests on its own, then again when combined with other drugs. The urgency of getting these Spring/Summer 2013 P at h s answers runs up against the slow and deliberate pace of clinical trials, which require enrolling hundreds of patients – whose tumors have various genetic characteristics – and testing drugs for months or years to see if they are effective. “If patients in clinical trials don’t live longer, we say the drug failed but we don’t know why it failed,” notes Keith Ligon, MD, PhD, of DF/BWCC’s Center for Molecular Oncologic Pathology (CMOP). “Maybe the drug killed off only half the cells, but in fact we did make some progress with the other part of the tumor. But we have no way to tell, other than crude measures that take months to demonstrate results.” Determined to do better, investigators are working on ways to shortcut the testing process, evaluate more quickly whether experimental drugs are reaching targets in the brain, and personalize treatments of Progress 27 grows as new patients come to DF/ BWCC for treatment. “We take out samples and try to establish a living model of that patient’s actual tumor, so that instead of trying to guess from its genetic profile how the tumor will behave, we try to have a model so we can go after it in a more direct fashion,” explains Ligon. “These tumor lines are an invaluable resource for preclinical testing, to make sure the drugs do what they are supposed to do,” notes David Reardon, MD, medical director of the Center for NeuroOncology. Reardon, Wen, and Ligon are currently designing clinical trials based on evidence from such studies to help pick drugs with the most promise. Developing Patient ‘Avatars’ With brain tumor cells from the Living Tissue Bank, Ligon has begun work on another type of personalized cancer medicine known as patient “avatars.” In online gaming, an avatar is an image that represents a person. In medicine, an avatar is an exact animal model of a single individual’s disease – such as a brain tumor – created to enable personalized drug research for that patient. Scientists create avatars by injecting mice with tumor cells from the living tissue bank or even tissue fresh from the operating room. If all goes well, an exact copy of the patient’s tumor will develop in the mouse. Additional mouse models can be created from the initial avatar, so that a variety of drugs can be tested on Using a Living Tissue Bank One of the newest and most advanced resources is on the second floor of Dana-Farber’s Jimmy Fund Building, where incubators and freezers contain cells taken from almost every DF/BWCC patient who undergoes surgery for high-grade brain tumors, such as glioblastoma. Five years ago, Ligon, with the support of his colleagues in NeuroOncology, started this collection of brain tumor cells that survive indefinitely as a resource for the DF/ BWCC Brain Tumor Program. He calls it the “Living Tissue Bank” in contrast to conventional tissue banking, which has focused on freezing or storing tissue in a form where the cells are no longer alive. Not all brain tumors can be grown in laboratory dishes, but the bank currently has 50 or 60 permanently established cell cultures, or cell lines, they can mine for valuable information. The bank continually 28 P at h s of MIT researchers designed this tiny microfluidic chip that can measure the mass and density of single cells, and how they respond to drugs. Progress / Spring/Summer 2013 www.dana-farber.org Photo courtesy of the Manalis Lab at MIT for patients who are racing against the clock. What if different drugs could quickly be tried in an exact animal model of a patient’s brain tumor, with results guiding the treatment of that patient? Could physicians remove a small number of cells from the tumor during surgery and rapidly screen a panel of drugs for their effectiveness? Are there better ways to predict whether a drug will cross the barrier that protects the brain, so that it can reach the tumor? Though none of these are ready for prime time, Center for NeuroOncology scientists and colleagues are hopeful that these strategies will prove valuable in the fight against stubborn glioblastomas. the tumors growing in the avatars. Ligon notes that this strategy is well-established in microbiology, where doctors take a sample of bacteria from a patient with an infection and grow them in a petri dish, trying different antibiotics to find one that kills the bacteria that is causing disease in the patient. “The ideal situation would be if we could do this fast enough – if we could test not just the drug the patient was prescribed, but all the drugs he or she could possibly be given” to weed out those that would be ineffective, Ligon says. The model could evaluate new drugs fresh from pharmaceutical company laboratories. Many scientists are skeptical that mouse avatars will prove valuable and cost-effective; Ligon agrees that the method is a long way from being proven. One hurdle is that not all tumor samples grow well in mice. Also, the process in its current form may take too long to help patients with rapidly growing brain tumors during their lifetime. In addition, the expense of creating and maintaining the mouse models is high. Ligon notes, however, that patients are increasingly interested in having avatars made of their disease. He is optimistic that this concept, originally tried in the 1960s, has a future. “Our models are more sophisticated and we have a lot more drugs to test than were available back then,” he says. A Cell-by-Cell Approach Ligon, who is also affiliated with the Neuro-Oncology Program of the Dana-Farber/Harvard Cancer Center, has begun exploring a futuristic scenario: subjecting one or a few cells isolated from a patient’s tumor to precise tests that might predict the tumor’s behavior and how it will respond to different drugs. Because tumors often have more than one type of cancer cell – tumor heterogeneity – the ability to test cells from different parts of the cancer could be extremely valuable. “Potentially we could take tumor cells right out of patients and analyze them almost immediately to determine what kind of drug to give them,” Ligon says. Such a shortcut may seem far-fetched, but Ligon is pursuing this vision in collaboration In neuro-oncology, many drugs fail because they can’t breach the “bloodbrain barrier” – tiny blood vessels that protect the brain. with Scott Manalis, PhD, a bioengineer at Massachusetts Institute of Technology (MIT) and a member of the David H. Koch Institute for Integrative Cancer Research. Manalis has created a microfluidic system so sensitive that it can measure the mass of a single cell. Within a few minutes, the device can tell, from changes in the mass and density of the cell, whether the cell is dormant, growing, or shrinking. And it can even tell scientists how the cell’s growth varies at different times – its “growth profile.” “If the mass goes up, the cell is Spring/Summer 2013 P at h s happy and growing,” says Ligon, “so if you apply the drug to a tumor cell and its growth profile doesn’t change, you know the drug had no effect.” If, however, the cancer cell’s growth stalls or shrinks, the drug is likely to be working. In a 2011 experiment at MIT, the system was tested on leukemia cells that were treated with an antibiotic drug. Less than an hour later, the weighing device detected a change in the cancer cells’ density, signaling that they were beginning to die. To the scientists, this suggested the potential value of the system in screening cancer drugs. Ligon’s collaboration with Manalis has been under way only a few months, but he is excited about the possibilities of measuring drug effects in real-time. “If we get the technology working, it would go into clinical trials to validate it; eventually it could be a diagnostic test.” Funds for the research come from a special National Institutes of Health program to support scientists who are asking “provocative questions” rather than continuing incremental, “safe” research. In another slant on analyzing the genome of single brain tumor cells, Dana-Farber’s Matthew Meyerson, MD, PhD, and Ligon are collaborating with chemical engineer Christopher Love, PhD, of MIT in a “Bridge Project” supported by the Koch Institute and Dana-Farber/ Harvard Cancer Center. “We now are using technologies which can take a single cell from a patient’s tumor, amplify it to make more DNA, and sequence its entire genome,” Ligon explains. With such precise information, scientists might be able to determine the genetic of Progress 29 Shown here is a “patient avatar” brain tumor (dark blue areas) within a mouse brain, created by implanting tumor tissue from a patient. makeup of the exact cells within a brain tumor found, in devices like those Manalis has developed, to use a specific mechanism for resisting drugs. And if the tumor is made up of several kinds of tumor cells, this technique could guide physicians in selecting multiple drugs – combination therapy – for the attack. Crossing the Barrier The most potent anticancer drug is worthless if it can’t reach its target. In neuro-oncology, many potentially effective drugs fail because they can’t penetrate the “blood-brain barrier” – tight-fitting blood vessel cells evolved to protect the brain against bacteria and poisons. A new tool being developed by DF/BWCC researcher Nathalie Agar, PhD, can track a drug as it enters the body and flows through the brain’s circulation, revealing whether molecules of the drug are getting through the barrier. With the power of mass spectrometry, which detects molecules by their mass, Agar has created a platform that creates images of a drug’s distribution in the body and the brain after the compound has been infused into a research animal. What’s new about Agar’s method is that there is no need for the drug molecules to be tagged with fluorescent chemicals, which can change the drugs’ structure, she says. (See “Tech Preview” on page 31 for details.) Agar and Dana-Farber colleague Charles Stiles, PhD, are using her mass spectrometry technique to determine if experimental drugs are able to breach the blood-brain barrier and reach tumor targets within the brain. Stiles, who is co-leader of the Dana-Farber/Harvard Cancer Center 30 P at h s of Neuro-Oncology Program, remembers the first time he saw Agar demonstrate her technique. “She showed me what she was doing with the mass spec technology, allowing us to visualize the inside of a blood capillary and drugs getting into the interstitial space [of the brain], and I was just blown away,” he says. “An especially powerful feature of Nathalie’s technology is that it does not require any radioactive or fluorescent labeling of the drugs being tested,” Stiles explains. “She can image the exact forms of drugs that are intended for use in patients.” Stiles and Agar discovered, in one experiment, that a drug did penetrate the barrier and could be seen on the computer display to have accumulated in the tumor. But the image also showed that the drug was confined mainly to the network of blood vessels that the tumor had created. “So the drug was just sitting there,” she says, “rather than reaching the tumor tissue itself.” Another interesting finding: The mass spectrometry system took 25 cross-section images of a mouse brain and created a 3-D representation. “We found that there was one region of the brain where the drug crossed the bloodbrain barrier more efficiently,” says Agar, which might lead to a strategy for delivering the drug Progress Spring/Summer 2013 where it is most likely to reach a tumor. One way of using the method clinically, Agar says, would be to give a drug to a brain tumor patient prior to surgery. The mass spectrometry image could then be used to study the tumor tissue that’s been removed “to see if the drug actually made it to the tumor.” If so, it would be a good sign for further treatment with the drug. Agar says she and Stiles, together with Dana-Farber chemist Nathanael Gray, PhD, plan to use the system to test more drugs from pharmaceutical companies. If they can demonstrate that certain drugs do reach the brain, she says, it “might be a very effective way to convince companies of the value of developing trials that could help us re-purpose existing drugs to treat brain cancer.” Only time will tell what impact these innovations – mouse avatars, single-cell testing, mass spec studies of drug penetration, and others – will have on the treatment of brain tumors. But one thing is certain: They reflect the power of collaboration among DF/BWCC investigators, both basic and clinical, to mount an intense effort against this stubborn form of cancer. See how the microfluidic chip works. Visit www.bit.ly/15OVxST. www.dana-farber.org Tech Preview Seeing with Mass Spectrometry New tools aid brain tumor studies B by richard saltus y measuring the mass of molecules, Nathalie Agar, PhD, makes images. With a mass spectrometry platform, Agar can trace the flow of cancer drugs given to research animals, noting whether they slip through the “blood-brain barrier,” tight-fitting blood vessels that keep chemicals from reaching the brain. For her studies of drug penetration in tumors and in classifying tumor types, the mass spectrometry platform measures the distribution of proteins, lipids, and other specific tissue components. From these measurements, computers can construct vivid images, including 3-D views of the blood-brain barrier. In a clinical trial, mass spectrometry technology is enabling Agar, in collaboration with Dana-Farber researchers, to examine brain tumors removed from patients to determine whether drugs given before surgery hit their tumor targets. She’s developing a GPS-aided mass spectrometry instrument that would guide neurosurgeons during an operation so that a brain tumor could be removed more extensively with ultimate preservation of healthy tissue. Agar directs the Surgical Molecular Imaging Laboratory at Brigham and Women’s Hospital, and also has an appointment in Cancer Biology at Dana-Farber. A major goal of her research is to provide more and better data to personalize treatments for brain tumors and other cancers. Agar, who holds a PhD in chemistry, and Charles Stiles, PhD, a Dana-Farber cancer biologist, are testing potential brain tumor drugs for their ability to cross the blood-brain barrier. Agar’s technique allows researchers to track a drug’s location after it is administered, without the need for costly, cumbersome fluorescent or radioactive dyes. Agar is also collaborating in a study of brain tumors caused by the spread of malignant cells from breast cancers. “We’ll use the mass spectrometer to examine tissue samples removed during surgery to see if the drug is getting into the tumor and how it’s distributed,” explains Agar. Much of her research, she says, is aimed at designing better treatments by analyzing different tumor cells and matching them to the most effective drugs. “But the first thing we need to determine is whether the drug makes it into the tumor – this is a fundamental question.” By Robert Levy Nathalie Agar, PhD, uses an advanced mass spectrometry platform to create images of cancer drugs flowing in the brain. Spring/Summer Spring/Summer 2013 2013 P at h s of Progress 31 Why I Work Here STACY KENNEDY, mph, rd by Richard Saltus S he is a fountain of nutritional advice, a fitness instructor and personal trainer, a self-proclaimed science nerd, and an advocate of healthful eating who walks the walk. “I’m about 90-percent vegetarian,” says Stacy Kennedy, MPH, RD, senior clinical nutritionist at Dana-Farber/ Brigham and Women’s Cancer Center (DF/BWCC). “My diet is basically plant-based, but sometimes I’ll make a big salad with a little bit of grass-fed beef, wild fish, or organic chicken.” She’s long been a “juicer,” augmenting her fruit and vegetable intake with home-pressed juices. Despite this, Kennedy is not a fanatic: “You still have to have balance and be a normal person and enjoy a piece of cake once in awhile,” she says. Kennedy, who holds a master’s degree in public health and is a registered dietitian and a certified specialist in oncology nutrition, came to DF/BWCC 12 years ago. She is one of six nutritionists in the department of Nutrition Services, where she helps cancer patients and survivors who want to manage their weight, design a more healthful diet, and learn how to “fight cancer with a fork” – nutritional strategies for cancer prevention, to promote survivorship and symptom management. “I spend a lot of time with patients trying to put it all into perspective,” she notes. “Nutrition can have a big impact on people with cancer, and it’s never really one thing – you need to find a system that works for you.” DF/BWCC is a great fit for Kennedy, who helped take care of her grandmother as she was dying from lung cancer, and who has long been interested in the field. ”There is a lot of interesting science and research about nutrition and oncology, and I love that,” she says. That’s an asset for Kennedy: When evaluating the ever-changing research “Nutrition can have findings on nutrition and cancer, as well as the a big impact on people claims put forth for all with cancer, and kinds of diets and herbs and supplements, she it’s never really one looks first and foremost thing – you need to to the scientific evidence. “We’re so inundated with find a system that these things, and everyworks for you.” one is interested in the most exciting, latest promise of a quick fix,” she says. “I tell my patients they don’t need to be afraid to talk about these unproven diets – I want to be supportive and informative, but it’s got to be safety first, efficacy second.” A project that Kennedy initiated several years ago – creating a nutrition information section on DanaFarber’s website – has evolved and, in early 2013, spawned a new iPhone app called Ask the Nutritionist: Recipes for Fighting Cancer. The app offers searchable questions about diet and cancer, as well as hundreds of recipes for use by cancer patients, people on specialized diets, and anyone interested in healthy eating. Stacy Kennedy, MPH, RD 32 P at h s of Progress Spring/Summer 2013 www. What I Know TIMOTHY ROURKE As Told to NAOMI FUNKHOUSER A sound on the baby monitor awoke Timothy Rourke and Mel Pepin at 6 a.m. on Father’s Day in 2006. The parents of then-15-month-old Declan Rourke rushed to find their child having a seizure. They sped their unconscious son to the hospital. Hours later, Declan was diagnosed with atypical teratoid rhabdoid tumor (AT/RT), a rare cancer that affects the brain and central nervous system. Just 32 American children under age 3 are diagnosed annually with AT/RT. Prior to 1997, mortality from such tumors was 100 percent within six months of diagnosis. Declan’s rigorous treatment at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC) included 52 weeks of cytotoxic chemotherapy agents delivered in adult doses, and six weeks of cranial radiation. He completed treatment in late 2007. “he is a normal, Today, Declan is almost 8, with no evidence of disease. happy kid, in the “He is a normal, happy kid, face of something in the face of something extraordinary,” says his father. extraordinary.” One of a handful of pediatric patients worldwide without a relapse or secondary cancer, Declan is one of the world’s only longtime survivors of AT/RT – a gift of life Rourke credits to “his friends and partners” at DF/CHCC. He gives this advice to those who face the prospect of being a parent of a cancer patient. Help your child guide the conversation. As a result of treatment, Declan suffers from hearing loss. He brought hearing aides to class for “show-and-tell.” We will equip Declan as his peer group dynamics change, to discuss his cancer, or not – his choice. Support and recognize the experience of being a caregiver. Mel quit her job to become Declan’s caregiver during treatment. We focused on patience, listening, and good communication. You’re a click away from a mom or dad who went through this. Log on and connect with other parents who also faced complicated choices. Never regret any decision you make. You are doing the best you can for your kid. It’s amazing what humans are capable of when you don’t have a choice. For parents, you discover within you this drive that you will do anything for your child. With a cancer diagnosis, the whole world rallies around you. It can be uncomfortable to ask for help. Accept it with gratitude. People feel helpless. Be directive in what you need. Decide to not live with cancer. Once we were on the survivorship journey, we decided not to live with the “what-ifs.” We reclaimed a goal in our life [adopting a child] that we had been ready to walk away from. We got through. For a long time, we thought we’d never get there. Celebrate. I feel lucky for every single day. Anything he does, I celebrate, because I almost didn’t have it. Timothy Rourke and his son, Declan Spring/Summer 2013 P a t h s of Progress Legislative Update What I Know New Law Reflects the Changing Face of Cancer Treatment Oral chemotherapy law brings parity to Massachusetts patients by Eric Schuller Massachusetts Gov. Deval Patrick signed an oral chemotherapy parity bill into law earlier this year, joining more than 20 states requiring health plans to cover oral cancer pills “at a rate no less favorable” than standard intravenous (IV) chemotherapy. The legislation ensures that patients who receive oral chemotherapy treatment will get the same insurance coverage as those who take it intravenously. Insurers generally cover IV chemotherapy as a medical benefit – with a modest patient copay and a limit on annual out-of-pocket costs – while oral chemotherapy is treated as a prescription drug benefit, requiring some patients to pay a significant portion of the drug’s cost, with no annual out-of-pocket limit. The new law has the potential to trim thousands of dollars in out-of-pocket costs for cancer patients receiving their chemo as a pill. “The parity provided by this bill is a recognition that cancer treatment is changing,” says Dana-Farber President Edward J. Benz Jr., MD. “Increasingly, pills are replacing IV chemotherapy in the clinical setting, and some newer cancer drugs are only available in pill form. In fact, New Massachusetts legislation makes it easier and cheaper for cancer patients to recieve oral chemotherapy and related anticancer medications. 34 P at h s of Progress since 2012, eight of the 11 oncology drugs approved by the FDA are oral treatments with no IV equivalent.” While chemotherapy pills and capsules have been around for years, they have become more common in the past decade, and experts see them as a critical part of cancer treatment in the future. For example, the drug imatinib (brand name Gleevec), which is the most effective treatment for chronic myelogenous leukemia, is only available in pill form, as is a newer medication, lenalidomide, which is used to treat multiple myeloma and myelodysplastic syndromes. Oral medications account for around 25 percent of 400 cancer medicines currently in development, according to a 2008 report from the National Comprehensive Cancer Network. And researchers are continuing to uncover new potential benefits that may be gained through the use of targeted medications available only in pill form. Passage of the Massachusetts legislation represents a victory for Dana-Farber’s Legislative Action Network, whose members have actively lobbied legislators to enact the bill since it was first introduced in 2009. “It’s a real victory for those who support patient access and equity,” says Anne Levine, Dana-Farber’s vice president of External Affairs. “In a state that rightly prides itself as leader in ensuring health care access to all, this is a positive step forward, and I’m hopeful that our members helped sway legislators to make the right decision in passing this bill.” To learn more about the Legislative Action Network or to join its ongoing advocacy efforts for legislation and policies that improve the lives of cancer patients, sign up for email action alerts at www.dana-farber.org/ legislative-action-network. Spring/Summer 2013 www.dana-farber.org 2012 A n n ua l R e p o rt /T r e a s u r e r ’ s R e p o rt and D a na -F a r b e r G ov e r na n c e A message from Chief Financial Officer Karen Bird Fiscal year 2012 was a very positive one for Dana-Farber, with the completion of the first full year of operations for our Yawkey Center for Cancer Care. We achieved an operating margin target of $15.3 million, or roughly 1.5 percent, compared to a budgeted gain of $5.9 million. This strong performance in 2012 continues our historic operating margin performance after a one year deficit in 2011. Total cash and investments grew by $93.9 million thanks to several factors: strong operating performance, strong fundraising activity, and a 12 percent return on our portfolio for the 12-month period ended Sept. 30, 2012. One other highlight: Our net assets grew to just over $1 billion this year. Strong growth in our patient care activities resulted in growth in patient care revenues of 11.5 percent. Thanks to the continued support of our donors, it was also a strong year for fundraising, which saw a 2.9 percent increase in unrestricted giving. Research revenues declined 8.4 percent, largely as a result of the expiration of government stimulus funds initiated in 2008. These stimulus funds created additional revenue that we expected to decline in 2012. This decrease brings research revenues back to our 2010 levels. Management this year entered into a lease for approximately 100,000 square feet of critically needed research space in the Longwood Center (near Dana-Farber, on the corner of Brookline and Longwood Avenues). The Longwood Center will open in 2015 and will give us the continued ability to recruit and retain world-class research faculty members. It also provides us with the unprecedented opportunity to reorganize the entire campus to accelerate the application of basic discovery and translational science to treatments that advance the basic and clinical science of cancer. Another exciting research advancement is Profile, our comprehensive personalized cancer medicine initiative launched in 2011 and operated in partnership with Brigham and Women’s Hospital and Boston Children’s Hospital. A key component of our broad personalized medicine initiative, Profile analyzes patients’ tumor tissue for nearly 500 genetic mutations in 41 cancer genes. This strategic initiative will provide one of the most complete profiles of known cancer genetic abnormalities available anywhere in the world. In 2012, we consented well over 70 percent of our new patients for this study and, during fiscal year 2012, we invested just over $2.4 million in this important initiative. Management, faculty, and staff throughout Dana-Farber – guided by the oversight of several committees of the Board of Trustees – worked diligently to achieve these results. We are grateful to them, and also to the many donors and friends of Dana-Farber who continue to demonstrate their commitment to the organization with their valuable knowledge and generous contributions, even in these challenging times. We are proud of all of these efforts and grateful for your strong and ongoing support. Annual Report 2012 P at h s of Progress 35 D a na -F a r b e r C a n c e r I n s t i t u t e I n c . and Subsidiaries* Condensed Consolidated Balance Sheets For the Fiscal Year Ended Sept. 30 2012 2011 (Dollars in thousands) Assets Current Assets 248,483 Investments 621,266549,397 Debt Service Reserve and Construction Fund Property, Plant, and Equipment, net Contributions Receivable, less current portion Other Assets Total Assets 201,452 13,209 9,173 644,775 656,888 55,786 61,365 21,529 9,347 $1,605,048$1,487,622 Liabilities and Net Assets Current Liabilities 174,255 166,734 Long-Term Debt and Other Liabilities 394,630 379,805 Net Assets Unrestricted 477,225 445,625 Temporarily Restricted 406,939 351,538 Permanently Restricted 151,999 143,920 Subtotal Net Assets1,036,163 941,083 Total Liabilities and Net Assets $1,605,048$1,487,622 Summary Statistical Information (unless otherwise noted, includes adult and pediatric patients) Infusion Treatments 123,440 117,974 Outpatient MD Visits 225,479 212,908 Number of Licensed Beds (as of year-end) Adult Inpatient Discharges Clinical Trials (open to patients at Dana-Farber, 30 30 1,134 1,060 721 694 including therapeutic and nontherapeutic trials) * Subsidiaries include Dana-FarberInc. and Dana-Farber Trust. 36 P at h s of Progress / Annual Report 2012 www.dana-farber.org D a na -F a r b e r C a n c e r I n s t i t u t e I n c . and Subsidiaries Condensed Consolidated Statements of Operations and Changes in Net Assets Fiscal Year 2012 Income For the Fiscal Year Ended Sept. 30 2012 2011 (Dollars in thousands) Revenues Research 316,347 345,529 Patient Service, net 602,928 540,815 57,067 55,441 Unrestricted Contributions and Bequests Other Operating 16,709 16,504 Total Revenues Expenses $993,051 $958,289 Direct Research 271,767 292,839 Unrestricted Contributions and Bequests: 6% Direct Patient Care 394,297 368,871 Other Revenue: 1% Research: 32% Patient Service: 61% Indirect Total Operating Expenses Operating Income 311,676299,075 $977,740 $960,785 15,311 (2,496) Investment Return, net 18,928 Fiscal Year 2012 Expenses 8,279 Interest Rate Swap Agreement Net interest received/(paid) (5,518) Change in fair value Other (4,965) (5,536) (8,699) (349) (Deficit)/Excess of Revenues Over Expenses23,407 (8,452) Other 8,193 42,517 (Decrease)/Increase in Temporarily Restricted Net Assets 55,401 5,043 (Decrease)/Increase in Permanently Restricted Net Assets 8,079 8,347 (Decrease)/Increase in Net Assets Net Assets at Beginning of Year Net Assets at End of Year Research: 34% Patient Service: 49% Management and General: 17% 95,08047,455 941,083 893,628 $1,036,163 $941,083 5% of patient-care expenses is directed to Community Benefits Comparison of Private Support 200 150 The preceding selected consolidated financial data as of Sept. 30, 2012, and 2011 (except for the summary statistical data) have been derived from the consolidated financial statements of Dana-Farber Cancer Institute Inc., Dana-Farber Inc., and Dana-Farber Trust. These have been audited by Ernst & Young, LLP, independent auditors. 100 50 { ($ in millions) 0 In FY 2012, the Institute raised $168 million in new gifts and new pledges through its Division of Development and the Jimmy Fund, and through the Friends of Dana-Farber Cancer Institute. For accounting purposes, the financial charts reflect new gifts and new pledges calculated at present value, excluding commitments the Institute could not record due to conditionality. Annual Report 2012 P at h s of 2011 2012 Foundation Grants Permanently Restricted Temporarily Restricted Gifts for Current Use Unrestricted Contributions and Bequests Progress 37 D a na -F a r b e r C a n c e r I n s t i t u t e I n c . Corporate Officers Board Committees and C hairpersons Board Development Committees and Chairpersons Joshua Bekenstein Chairman Audit Committee John J. O’Connor Edward J. Benz Jr., MD President and Chief Executive Officer Committee on Facility Planning and Construction John L. Marshall III Gary L. Countryman Vice Chairman Communications Committee Harvey Rosenthal Marjorie B. Salmon Development Committee Charles A. Dana III Richard P. Morse James W. Rappaport (Co-Chair, Trustee Annual Fund) Jean S. Sharf (Co-Chair, Trustee Annual Fund) Richard P. Morse Vice Chairman Community Programs Committee Amy Z. Reiner Jerry M. Socol Vincent M. O’Reilly Vice Chairman Gift Planning Committee Barbara L. Sadowsky James P. Sadowsky Compensation Committee Gary L. Countryman Richard A. Smith Vice Chairman Executive Committee Joshua Bekenstein Brian J. Knez Treasurer Finance Committee Brian J. Knez Karen S. Bird, MPH Assistant Treasurer Governance Committee Neal J. Curtin, Esq. Neal J. Curtin, Esq. Secretary Investment Committee Robert Stansky Richard S. Boskey, Esq. Assistant Secretary Joint Committee on Quality Improvement and Risk Management Vincent M. O’Reilly Robert J. Sachs Kathleen Harkey Assistant Secretary Medical Staff Appointments Committee Gary L. Countryman Trustee Science Committee Malcolm S. Salter The governance listings in this annual report are current as of Jan. 1, 2013. 38 P at h s of Progress / Annual Report 2012 www.dana-farber.org D a na -F a r b e r C a n c e r I n s t i t u t e I n c . Trustees Andrea R. Abraham Gerhard R. Andlinger David Auerbach David E. Barrett Joshua Bekenstein 2* Robert Belfer Edward J. Benz Jr., MD 2* Roger Berkowitz * Amy S. Berylson * Armin G. Biller John F. Blais Betty Ann Blum Justice Stephen G. Breyer 1 Hon. Frederick L. Brown * Craig A. Bunnell, MD J. Gary Burkhead Kennett F. Burnes, Esq. Stephen J. Burton Richard A. Cantor Michael A. Champa * George Cloutier Marc A. Cohen * Joseph F. Cotter 1 Gary L. Countryman 2* Howard Cox* Neal J. Curtin, Esq. 2* Alice Cutler Charles A. Dana III * Lee S. Daniels Nader F. Darehshori * Laura Weissman Davis David A. Dechman Peter I. deRoetth Emily F. DiMaggio James H. Donovan James Dow John P. Dunfey Donald Dwares Michael R. Eisenson, Esq. Edward Eskandarian John S. Farber Stephen B. Farber Thomas A. Farrington * James L. Fine * Stephen A. Fine * Deborah S. First Robert C. First * Charles Forman Emil Frei III, MD Michael Frieze M. Dozier Gardner Arthur Gelb, ScD 2* Nancy Q. Gibson * William M. Gillen Michael S. Gordon Abraham D. Gosman * James D. Griffin, MD Richard Grubman * Judith Hale David V. Harkins 2* Marian L. Heard Francis Heller * Alan J. Hirschfield Thomas F. Holt Jr., Esq. Barbara H. Hugus, PhD 1 Alison Poorvu Jaffe Jane P. Jamieson * Glenn M. Johnson Hon. Scott L. Kafker * William S. Karol Stephen B. Kay Phyllis Swerling Kellem 1 Patricia D. Kelsey 1 Michele Kessler Michael J. Kittredge Brian J. Knez 2* Ruth Kopelman 1 Steven P. Koppel * Paul B. Kopperl * Stephen P. Koster, Esq. * Daniel A. Kraft Robert K. Kraft 2* Sandra G. Krakoff 2* Phyllis Krock Althea Lank Jonathan Lavine Kenneth H. M. Leet John J. Legere * Kenneth Levine Roger A. Lockwood * Richard K. Lubin 2* Bradley A. Lucas * Lawrence Lucchino Hildegarde E. Mahoney Peter A. Maich Roger M. Marino John L. Marshall III 2* Thomas J. May William F. McCall Jr. Joseph C. McNay * William F. Meagher * David S. Moross Richard P. Morse 2* David G. Nathan, MD * George Neale Charles Nirenberg Marci Noller Joseph E. Norberg * Brian O’Connor John J. O’Connor * Vincent M. O’Reilly 2* Stuart H. Orkin, MD Edward O. Owens * Peter Palandjian * Arthur M. Pappas, MD 1 Theodore Pasquarello * Jean F. Pearlstein 2* David B. Perini * Eileen Perini * Jennifer Perini * Steven P. Perlmutter, Esq. * Susan M. Poduska * Elizabeth Pohl * William J. Poutsiaka John M. Randolph 1 Kathleen M. Randolph, PhD 1 James W. Rappaport * John P. Reardon Jr. Shari E. Redstone Sumner M. Redstone 1 Amy Z. Reiner * Robert L. Reynolds * Barrett J. Rollins, MD, PhD Ann M. Rosenberg * Harvey Rosenthal 2* Edward F. Rover * Robert J. Sachs, Esq. * Barbara L. Sadowsky James P. Sadowsky Marjorie B. Salmon * Malcolm S. Salter * H. Terrence Samway Rebecca Sanders * Judith P. Schlager Richard N. Seaman Thomas Sellers Laura Sen * Paul J. Severino Jean S. Sharf Lawrence N. Shulman, MD Paula L. Sidman Richard A. Smith 2* Mrs. Susan F. Smith * Ruth F. Snider Jerry M. Socol * Gloria H. Spivak 2* Robert Stansky William Starr James M. Stoneman 1 Patrick J. Sullivan Ronald S. Sullivan Jr. * Jean C. Tempel * Beth F. Terrana * David T. Ting * Delores Barr Weaver J. Wayne Weaver Karen L. Webster T. Conrad Wetterau Gregory A. White Frederica M. Williams * Winnie W. Wong, Phd Carl Yastrzemski 1 George J. Yost III, Esq. * Mortimer B. Zuckerman 1 1 2 * + Honorary Trustee Member, Executive Committee Governing Trustee Deceased The governance listings in this annual report are current as of Jan. 1, 2013. Annual Report 2012 P at h s of Progress 39 D a na -F a r b e r C a n c e r I n s t i t u t e I n c . Executive Leadership Edward J. Benz Jr., MD President and Chief Executive Officer Karen S. Bird, MPH Chief Financial Officer and Assistant Treasurer Dorothy E. Puhy, MBA Executive Vice President and Chief Operating Officer Barrett J. Rollins, MD, PhD Chief Scientific Officer Susan D. Block, MD Chair, Psychosocial Oncology and Palliative Care Stephen E. Sallan, MD Chief of Staff Emeritus Richard S. Boskey, Esq. Senior Vice President; General Counsel; and Chief Governance Officer Craig Bunnell, MD, MPH, MBA Chief Medical Officer Lawrence N. Shulman, MD Chief of Staff; Senior Vice President, Medical Affairs; Director of Regional Development; and Director of Center for Global Cancer Medicine Steven R. Singer, MPA Senior Vice President, Communications Beverly R. Ginsburg Cooper, MBA Senior Vice President, Research Scott J. Swanson, MD Chief Surgical Officer George D. Demetri, MD Senior Vice President, Experimental Therapeutics Annick D. Van den Abbeele, MD Chief of Imaging James D. Griffin, MD Pasi A. Jänne, MD, PhD Philip W. Kantoff, MD Xiaole (Shirley) Liu, PhD Dennis C. Lynch, MD, PhD* Lee M. Nadler, MD Stuart H. Orkin, MD Giovanni Parmigiani, PhD Thomas M. Roberts, PhD Barrett J. Rollins, MD, PhD* Rosalind A. Segal, MD, PhD Jane C. Weeks, MD, MSc Department of Medical Oncology James D. Griffin, MD, Chair Department of Biostatistics and Computational Biology Giovanni Parmigiani, PhD, Chair Paul J. Catalano, ScD, Associate Chair Department of Cancer Biology James D. Griffin, MD Chair, Medical Oncology The governance listings in this annual report are current as of Jan. 1, 2013. Jay R. Harris, MD Chair, Radiation Oncology Research Leadership Department of Cancer Immunology and AIDS Deborah Hicks, MA Senior Vice President, Human Resources Professional Administration Harvey Cantor, MD, Chair Kai Wucherpfennig, PhD, Co-Chair Edward J. Benz Jr., MD President, DFCI; Director, DF/HCC Joseph O. Jacobson, MD, MSc Chief Quality Officer Beverly Ginsburg Cooper, MBA Senior Vice President, Research, DFCI; Associate Director, Administration, DF/HCC Philip W. Kantoff, MD Chief Clinical Research Officer Lee M. Nadler, MD Senior Vice President, Experimental Medicine Philip W. Kantoff, MD Chief Clinical Research Officer Stuart H. Orkin, MD Chair, Pediatric Oncology Barrett J. Rollins, MD, PhD Chief Scientific Officer Maria Papola, MHA Senior Vice President, Institute Operations Susan S. Paresky, MBA Senior Vice President, Development Patricia Reid Ponte, RN, DNSc, FAAN Senior Vice President, Patient Care Services; Chief Nursing Officer 40 P at h s of Progress Thomas M. Roberts, PhD, Co-Chair Charles D. Stiles, PhD, Co-Chair Department of Pediatric Oncology Stuart H. Orkin, MD, Chair Department of Psychosocial Oncology and Palliative Care Susan D. Block, MD, Chair Department of Radiation Oncology Jay R. Harris, MD, Chair * Ex-officio Executive Committee for Research William G. Kaelin Jr., MD, Chair Harvey Cantor, MD Alan D. D’Andrea, MD Levi A. Garraway, MD, PhD Beverly R. Ginsburg Cooper, MBA* Nathanael Gray, PhD / Annual Report 2012 www.dana-farber.org D a na -F a r b e r C a n c e r I n s t i t u t e I n c . Friends of Dana-Farber Cancer Institute Co-Presidents Lauren Frei* Marci Noller Vice Presidents Rebecca Latimore* JoAnne Marshall Cristina S. Peters* Dana Gerson Unger Treasurer Debbie Maltzman Recording Secretary Amye Kurson Governing Directors Suzanne Fisher Bloomberg Jen Cunningham Butler Blake Chanowski Kim Chisholm Alice Cutler* Sarah Duggan Jayne Bennett Friedberg* Susan Mendoza Friedman Micki Hirsch Nicole Hirsch Jane M. Holt* Marci Katz Audra Lank Maxene Lieberman Jane B. Mayer Jane R. Moss Jean F. Pearlstein* Rachel Police Lesley Prowda Nancy L. Socol* Members at Large Suzanne Chapman Tobi Marram Courtney Tatelman Susan Wilk Honorary Directors Jean Speare Canellos* Barbara Lapp Louise S. Shivek Susan F. Smith Marilyn N. Wolman Founding President Sheila Driscoll Cunningham** D a na -F a r b e r I n c . Program Manager Sarah M. Duggan Program Assistant Joniece Leonard Corporate Officers Art Program Coordinator Elaine L. Tinetti Joshua Bekenstein Chairman * Past President ** Deceased Edward J. Benz Jr., MD President and Chief Executive Officer Brian J. Knez Treasurer and Vice Chairman Trustee Chairs President’s Visiting Committees Karen S. Bird, MPH Assistant Treasurer Neal J. Curtin, Esq. Secretary Basic Science William Karol, Co-Chair Edward F. Rover, Co-Chair Gastrointestinal Cancer Center Michele Kessler, Co-Chair Peter Palandjian, Co-Chair Richard S. Boskey, Esq. Assistant Secretary Kathleen Harkey Assistant Secretary Trustees Hematologic Oncology Marc A. Cohen, Co-Chair Alan Hirschfield, Co-Chair Joshua Bekenstein Edward J. Benz Jr., MD Brian J. Knez Robert Stansky The Jimmy Fund Nancy Gibson, Co-Chair Patrick J. Sullivan, Co-Chair The Lank Center for Genitourinary Oncology Thomas A. Farrington, Chair Althea and Bertram Lank, Honorary Co-Chairs Dana-Farber Inc. manages the investments of Dana-Farber Cancer Institute Inc. The governance listings in this annual report are current as of Jan. 1, 2013. The Lowe Center for Thoracic Oncology William M. Gillen, Co-Chair Susan M. Poduska, Co-Chair Pediatric Oncology Alison Poorvu Jaffe, Co-Chair T. Conrad Wetterau, Co-Chair Susan F. Smith Center for Women’s Cancers Mrs. Susan F. Smith, Chair Jane P. Jamieson, Co-Chair Annual Report 2012 P at h s of Progress 41 Non-profit Org. U.S. Postage P A I D Dana-Farber Dana-Farber Cancer Institute 450 Brookline Ave. Boston, MA 02215-5450 617-632-4090 www.dana-farber.org A teaching affiliate of Harvard Medical School Young dancers visited Dana-Farber in December as part of a performance to benefit breast and ovarian cancer research. The visit was the result of the Friends of Dana-Farber’s partnership with the nonprofit Dancing for a Cure, which raises funds for cancer research.