yale cancer center
Thomas J. Lynch, Jr., MD 2 Director’s Letter Director research programs Kevin Vest, MBA, FACHE
Deputy Director, Administration and Clinical Affairs 16 Developmental Therapeutics features Turning Cancer’s Metabolism Against Itself Renee Gaudette 4 Director, Public Affairs and Marketing 4 Groundbreaking Immunotherapy 18 Cancer Prevention and Control Against Bladder Cancer The Growing Use of E-Cigarettes Among Youth A Phase I clinical trial has shown dramatic art + design response in more than 50% of patients with 20 Cancer Immunology advanced bladder cancer after using MPDL3280 Peter Baker Studios LLC How Immune Cells Go Rogue immunotherapy treatment. pbakerstudios.com 22 Molecular Virology 7 Paving the Way for The Future: Henry The Links Between HIV and Cancer Baker’s Tale of Triumph contributors Henry was just 2 years old when he was Writers 24 Cancer Genetics and Genomics diagnosed with acute lymphoblastic leukemia. Emily Fenton Blocking Metastasis in Breast Cancer He participated in a clinical trial, which was Steve Kemper developed to minimize long-term side effects Jill Max 26 Radiobiology and Radiotherapy without sacrificing cure. The Interconnected Mysteries of DNA Repair and
Photographer Breast Cancer 10 Integrating and Expanding Cancer Care Peter Baker Across Connecticut pbakerphoto.com 28 Signal Transduction Already the largest cancer care delivery Silencing the Signals that Lead to Melanoma 7 system in Connecticut, the Smilow Cancer Care Breakthroughs is published annually to highlight research and clinical advances from Network expanded this year to include two Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. more locations. leadership and membership Yale Cancer Center 12 A Surprising Defense Against 333 Cedar Street, PO Box 208028 30 Yale Cancer Center and Pancreatic Cancer New Haven, CT 06520-8028 Smilow Cancer Hospital at A recent study from Yale Cancer Center is the yalecancercenter.org Yale-New Haven Leadership first to demonstrate a link between the duration of aspirin use and decreased risk of © Copyright 2014, Yale Cancer Center. 32 Yale Cancer Center Membership pancreatic cancer. All rights reserved. No part of this periodical may be reproduced by any means,
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yalecancercenter.org | Yale Cancer Center 1 40& five November 2014 marked five years since NCCN guideline setting committees. patients and cancer survivors. PhD, whose laboratory is actively studying the stem cell the opening of Smilow Cancer Hospital at Yale-New Our research efforts in 2014 were headlined by continued I was very excited to welcome Patricia M. LoRusso, DO dynamics in hair follicles. Dr. Greco is anticipating their Haven! While our initial objectives of building a cancer progress in immunotherapy research. Mario Sznol, to our team in August as Associate Director of Innovative study can shed light on which cells and signaling pathways hospital that redefines excellence in patient-focused MD presented at ASCO on the long term efficacy of Medicine at Yale Cancer Center. Dr. LoRusso is widely go awry in the development of cancerous cells. care and research have been met we continue to find combination immunotherapy for patients with advanced regarded as a leading expert on developing new cancer new opportunities for translational research and ways melanoma, while Roy Herbst, MD, PhD and Daniel drugs through clinical trials and has already been a As we move into the New Year and our celebrations to make Smilow even better. At the same time, we are Petrylak, MD published in Nature on positive outcomes wonderful addition to our leadership team. She brings of five years of Smilow Cancer Hospital and 40 years also celebrating a significant milestone at Yale Cancer using immunotherapy treatment for both advanced lung more than 25 years of expertise in medical oncology, drug of Yale Cancer Center, we will continue to expand our Center - 40 years of our comprehensive cancer center cancer and bladder cancer. development, and early phase clinical trials to Yale. presence in Connecticut through our 11 Smilow Cancer Melinda Irwin, PhD Valentina Greco, PhD designation from the National Cancer Institute. The Hospital Care Centers and offer more innovative clinical combination of Smilow and YCC has allowed us to Cancer prevention research is a priority, with our With Dr. LoRusso’s focus on Phase I clinical trials, and our trial opportunities to our patients. I look forward to bring advances from our labs to expand the number of partnership with Yale School of Public Health as our redoubled effort on clinical research over the last several sharing new research advances and outcomes from our cutting edge treatment and prevention strategies available foundation. Melinda Irwin, PhD has built a national years with leadership from Dr. Howard Hochster, Dr. Roy laboratories and clinics with you in 2015. to our patients. reputation for her expertise on exercise and diet and Herbst, and Dr. Paul Eder, we have increased the number its impact on cancer and recurrence. Her most recent of patients participating in clinical trials at Smilow Cancer Sincerely, This past year, we were welcomed into the National publications, linking moderate exercise to reduce Hospital three-fold in three years. We plan to build on Comprehensive Cancer Network (NCCN) as a main recurrence rates in breast cancer survivors; quality of this momentum into 2015 and beyond. member institution. As many of you know, NCCN is a diet and mortality in ovarian cancer survivors; and Thomas J. Lynch, Jr., MD prestigious group of Cancer Centers who come together research that shows that exercise improves joint pain Finally translational research is based on advances in Director, Yale Cancer Center to set national guidelines for cancer care and I am pleased caused by aromatase inhibitors prescribed to breast fundamental tumor biology. In 2014, I can think of Physician-in-Chief, Smilow Cancer Hospital that our faculty can now share their expertise on the cancer patients, will change the way we counsel our no greater example than the work of Valentina Greco, Jonathan and Richard Sackler Professor of Medicine
Roy S. Herbst, MD, PhD Patricia M. LoRusso, DO
2 Yale Cancer Center | Year in Review 2014 yalecancercenter.org | Yale Cancer Center 3 Groundbreaking IMMUNOTHERAPY against bladder cancer
The therapeutic weapons against various cancers Program, and Co-Director of the Signal Transduction ligand 1) that is expressed by some patients’ bladder One of his patients, Peter Ehmer, now 44, was diagnosed have been multiplying rapidly, but for patients with Program and his colleagues tested a new antibody on 15 cancers. About half of the people in Yale’s study were in May 2013 with stage III bladder cancer. He had urothelial bladder cancer (UBC), the options have barely patients whose metastatic urothelial bladder cancer had positive for PD-L1 expression, and they responded most three months of chemotherapy and surgery to remove improved in 30 years. Worse, the standard chemotherapy not been reduced by chemotherapy, typically the final strongly to MPDL3280. PD-L1 binds to the surface of his bladder and prostate. He then participated in a treatment for UBC is too toxic for many patients, whose option for such patients. bladder cancer cells and sends out disinformation that different clinical trial at Yale. Nevertheless, two lymph prognosis is already poor, and although the majority of “We found a very high response rate,” said Dr. Petrylak. lulls the immune system into shutting down, which nodes continued to grow. After three treatments with patients initially respond, most relapse. These limitations “After twelve weeks of treatment, more than half of the allows the cancer cells to proliferate without interference. MPDL3280, he had a CT scan. may soon change if research on a new immunotherapy patients had at least a 50 percent decline in their tumor MPDL3280 prevents PD-L1 from binding to its receptors “Dr. Petrylak called within an hour,” said Mr. Ehmer, lives up to its exciting early promise. measurements. Two patients had complete disappearance and thus short-circuits its deceitful signals. The immune “to say that the lymph nodes had not just shrunk but The findings, which emerged from a Phase I trial at of the tumor. One patient had a cancerous lymph node in system wakes up, detects the cancer cells, and sends disappeared. I was very emotional. I called my wife right Yale Cancer Center and other international cancer his neck, which has completely disappeared; this patient T-cells to destroy them. away and shared the news with my two kids when I got centers, caused a stir in June at the annual meeting of had been on three previous chemotherapies. This was the The responses among the patients at Yale were not only home. I’ve been through a lot in the last year and a half, the American Society of Clinical Oncology and were first time we’ve seen this dramatic a response in patients dramatic, but also prolonged. The trial was designed to and it’s just such a weight off my shoulders.” published in November in Nature. at this stage of the disease.” treat the patients every three weeks for up to a year, but Mr. Ehmer also confirms another pleasing finding: the In Yale’s part of the trial, Dr. Daniel Petrylak, MD, The patients were treated with a new synthetic that has been extended, explained Dr. Petrylak, “because side effects of the new immunotherapy, mainly fatigue, Professor of Medicine and Urology, Clinical Research ‘checkpoint blocking’ antibody called MPDL3280. It the patients’ tumors are still responding, and because we are far less severe than those common in chemotherapy. Program Leader for the Prostate and Urologic Cancers targets a protein named PD-L1 (programmed death- really don’t know the optimal duration at this point.” These strong Phase I findings led the U. S. Food and
4 Yale Cancer Center | Year in Review 2014 yalecancercenter.org | Yale Cancer Center 5 PAVING THE WAY FOR THE FUTURE:
Drug Administration (FDA) to designate MPDL3280A a tricked by the cancer cells’ false signals. HENRY BAKER’S ‘breakthrough therapy.’ According to the FDA’s website, Dr. Petrylak recently completed a Phase II trial on this rare status “is intended to expedite the development MPDL3280A at Yale, but can’t yet discuss the findings. Tale of Triumph and review of drugs for serious or life-threatening He foresees most bladder cancer patients using conditions.” It is given only when early clinical evidence MPDL3280A in conjunction with chemotherapy. For demonstrates that a therapy “may have substantial patients who can’t tolerate chemotherapy, however, the improvement on at least one clinically significant new antibody could become a first-line treatment. “We endpoint over available therapy.” Since decades have need to sort out the factors that will lead to a response passed without much progress in the treatment of and give patients a durable response,” said Dr. Petrylak. urothelial bladder cancer, and since another 74,000 Dr. Petrylak’s next step is to look for the optimal Americans will be diagnosed with bladder cancer in 2014, sequences and combination of therapies, including breakthrough therapies are desperately needed for this surgery, MPDL3280A, and chemotherapy. “We’re going disease. to do a variety of sequencing trials to see how we can best MPDL3280A is the newest of several anti-PD1 therapies utilize this antibody,” said Dr. Petrylak, “such as bringing designed to silence the false signals that turn off the in the drug prior to surgery.” He expects these trials to be immune system’s radar and allow some cancers to grow. underway within a year. Other trials at Yale have found that anti-PD-1 therapies “Immunotherapy,” he added, “is the most exciting area Peter and Alaina Ehmer are effective against melanoma, kidney cancer, and non- of genitourinary cancer research. I can see this becoming small cell lung cancer. One of these drugs, nivolumab, was the standard of care at some point. It’s changing the recently approved in Japan for treatment of melanoma. whole field.” Like MPDL3280A, nivolumab works by thwarting PD-L1, which allows the immune system to switch back on and “Immunotherapy is the most exciting area of genitourinary cancer Henry Baker dramatically shrink tumors. The effects of the antibodies research. I can see this becoming the standard of care at some point. It’s can be long-lasting; the therapies may cause the immune system to produce ‘memory lymphocytes’ that aren’t changing the whole field.”
6 Yale Cancer Center | Year in Review 2014 yalecancercenter.org | Yale Cancer Center 7
Jenna and Brendan Baker were faced with to watch out for, and how to care for him. Henry was too the population is small, and the importance of participating in a trial some good would come from Henry’s fears and anxieties that any the most difficult challenge of their life when young to tell us exactly what he was feeling, so we had to be collaborating with other institutions.” journey and he would have an impact on the future. parent would have.” their seemingly healthy two year old son was diagnosed vigilant, and they gave us the tools to do that.” Henry had a central line and port put in for easier blood Jenna and Brendan commented that when your child Now six years old, Henry with cancer. He went to the pediatrician with a fever that ALL is a fast-growing cancer of lymphocyte-forming draw and to avoid any damage to his surrounding tissue has cancer it is an incredible stress on every aspect of likes to share his story with was not responding to the normal remedies. Results of a cells called lymphoblasts. Around 80 percent of children during chemotherapy. Henry’s parents were taught how life. Henry was going through the treatments, but they others and has even spent blood test raised suspicion for cancer and immediately are diagnosed with pre B-cell ALL as opposed to T-cell to handle the port to avoid infection, and Henry received took on the mental burden as if they themselves had time in the classroom with Henry was sent to the Emergency Department at Yale- ALL, and the “pre-B” form of ALL is the type Henry was oral chemotherapy at home every day, and intravenously cancer. Henry has a twin sister and two older sisters that Yale medical students. For New Haven Children’s Hospital where doctors confirmed diagnosed with. Henry’s presenting age, white blood cell through his central line at the hospital periodically were in 2nd and 5th grade when he was diagnosed. The him, this has been life up his diagnosis. Acute lymphoblastic leukemia (ALL) they count, and leukemia subtype, qualified him for a clinical for 40 months. Pediatric Hematology and Oncology team partners until now. Henry went to were told, which at the time meant nothing more to them trial through the Children’s Oncology Group (COG). “It was very stressful to have to make the decision to put with psychologists, psychiatrists, social workers, and school as much as possible, than the fact that their son was sick, and they were in for The COG enables members of the Yale Pediatric Henry on a clinical trial,” said Brendan. “When you hear child life specialists who offer an array of psychosocial which is always a high priority the fight of their lives. Hematology and Oncology Program to work the term childhood cancer you think you have an idea services to children receiving cancer care, along with of Dr. Kupfer’s for his patients. His parents commented “You don’t get the level of care we Thankfully, Dr. Gary Kupfer, Professor of Pediatrics cooperatively with other academic health centers to of what you are in for, but we really had no idea. Living their families. They talked with Henry’s older sisters and that although he does not fully comprehend what he went received just anywhere. It was truly (Hematology/Oncology) and of Pathology, and Section conduct large-scale studies. Because childhood cancer close to New York City and Boston, we met with other explained things in a way they could understand, and through right now, some day he will and the courage and Chief of Pediatric Hematology/Oncology, was on call that is relatively rare, medical centers must work together to doctors, but realized that Smilow was a special place. We answered their questions. strength he showed at such a young age will be fuel for him. amazing and everyone knew Henry as night, and met with Henry and his parents. Henry spent compile enough data. Yale’s participation also ensures were confident that our son was not only getting the best Dr. Kupfer explained that a large part of his role is to “We are still healing as a family a year after his last a little boy, not as a cancer patient.” 10 days in the hospital, most of which was focused on access to the newest and best treatments available. possible medical care, but also the best comprehensive care guide the family through all of the difficult decisions and treatment. It is a process and will always be a part of getting him strong enough for treatment. “There is a long history of clinical trials in pediatric that included us as a family.” treatments. The bond formed goes beyond the typical our lives. The effect is widespread and every hug means how none of this would have been possible without Dr. “During Henry’s time in the hospital it was about his oncology,” remarked Dr. Kupfer. “It is very different Henry responded very well to the treatment protocol, doctor-patient relationship that he learned about in medical something different, every puzzle on the floor, every Kupfer and his team. You don’t get the level of care care and getting him ready for treatment, but also about when compared to adult cancer care. Clinical trials which was developed to minimize long-term side effects school. “You are caring for, and hopefully curing their child moment spent with my children is precious,” said Brendan. we received just anywhere. It was truly amazing and educating us on what this all meant. We didn’t feel lost once first began with pediatric patients and in 1948 agents without sacrificing cure. Henry’s parents felt comfortable of a life-threating illness, and you cannot help but become Jenna commented, “It is a part of who Henry is and everyone knew Henry as a little boy, not as a cancer we were sent home, which was so important,” said Jenna. given to pediatric patients became the first drugs to that a clinical trial was the right thing for their son, not connected, and this is a very special family. They rose to the who he will become. We talk about it as much as he patient. They carried us through the darkest time, and H“They made sure to fully educate us on what symptoms induce remission in children with ALL. We recognize only because of his type of cancer, but also because by challenge that was put in front of them, despite the normal wants, without dwelling on it. We can’t help but think for that we are forever grateful.” 108 Yale Cancer Center | Year in Review 20141 Byalecancercenter.org | Yale Cancer Center 9 Integrating and Expanding CANCER CARE ACROSS CONNECTICUT said Anne Chiang, MD, PhD, Chief Medical Officer clinical questions that require this kind of participation. increased from about 30 to about 180 since launching the for the Network and Assistant Professor of Medicine Besides clinical research, integration across the Smilow Network in 2012. (Medical Oncology). “There’s a degree of confidence from Network has brought a host of initiatives aimed at The push to standardize care across the Network has both the main campus and faculty physicians on site to improving the quality of patient care and safety. One involved implementing a single electronic medical record feel comfortable opening trials.” She noted that earlier example is the innovative telepharmacy model developed across the sites, as well as an effort to improve quality. this year, a Care Center recruited the first patient to the to provide sites with the same high pharmaceutical Smilow participated in the American Society of Clinical national Lung-MAP trial, a groundbreaking study for standards available at Smilow Cancer Hospital. In this Oncology’s Quality Oncology Practice Initiative (QOPI), patients with advanced squamous cell lung cancer that is program, a central team of pharmacists oversees the a quality assessment and improvement program aimed expected to involve more than 200 medical centers during preparation of chemotherapeutic agents by technicians at promoting excellence in cancer care. The Smilow the next five years. at the Care Centers, freeing the on-site pharmacists to Cancer Care Center in Waterbury has received QOPI Participating in a clinical trial used to mean that patients provide personalized care. This initiative earned Yale- certification and Smilow recently applied for certification would have to leave the care of community physicians, New Haven Hospital the 2014 Award for Excellence across the entire Network. Identifying, developing, and a barrier to accrual that is particularly challenging in in Medication-Use Safety by the American Society of implementing such improvements across the Smilow minority populations, where participation in adult cancer Health-Systems Pharmacists. Network widely benefits patients and has already trials is just three percent. “I have patients who never would The Network also provides patients with access to increased patient satisfaction. Already the largest cancer care delivery system in Connecticut, the Smilow Cancer Hospital Care have thought about participating in clinical research who subspecialty expertise that would not otherwise be Efforts over the last two years to integrate the Care Center Network expanded earlier this year. Its 11 locations are fully integrated with Smilow Cancer Hospital at Yale-New have been able to get a cutting edge molecular test that available locally. “One of the biggest advantages of Centers, refine the transition from community practices, Haven, offering the world-class cancer care and clinical research for which Smilow is widely recognized. they never would have been able to afford,” said Andrea this affiliation is it allows us to care for patients in the and build the infrastructure for operations, quality, and In September, Oncology Associates of Bridgeport (OAB), PC, joined the Smilow Network with offices in Trumbull and Silber, MD, an oncologist at the Smilow Cancer Hospital community while feeling fully supported in terms of clinical research have resulted in an integrated N etwork Fairfield. The five OAB physicians continue to see patients in these locations, which have been undergoing renovations Care Center on Yale-New Haven Hospital’s Saint Raphael rare cancers or common cancers when there are areas with 28 oncologists, 250 staff members and over 7,000 and expansion to provide improvements that would have otherwise been impossible, such as on-site pharmacy services, Campus in New Haven. “It’s different when they’re of uncertainty as to the optimal treatment,” said Neal visits to Care Center medical oncologists per month. upgraded facilities for chemotherapy infusion, and improved safety standards. participating in a trial with doctors and nurses that they Fischbach, MD, a medical oncologist who practices in “Now we’re moving into the exciting second phase,” said Integrating with Smilow has brought increased clinical research activity to all of the Care Centers, with clinical trial know.” Almost half of the patients in her practice are the Trumbull and Fairfield locations. The number of Dr. Chiang, “where we’re starting to see the benefits and accrual more than doubling in 2014. “The Care Center faculty are incredibly motivated and real champions for research,” from diverse populations and are helping to answer many cases presented at tumor boards from the community has growth of what has been planted.”
1 010 0 Yale Cancer Center | Year in Review 20114 yalecancercenter.org | Yale Cancer Center 1211 A Surprising Defense Against PANCREATIC CANCER
On the National Cancer Institute’s list of A study published last summer by Harvey Risch, MD, reduced their risk of pancreatic cancer. The study also study were three times more likely to be diagnosed with the twelve most common cancers in the U.S., pancreatic PhD, Professor of Epidemiology, and several colleagues uncovered a correlation between the length of time that pancreatic cancer than those who continued the regimen. cancer ranks twelfth in terms of estimated new cases, signals a promising, inexpensive possibility for changing people took aspirin and the amount of protection they It has long been known that daily low-dose aspirin can with 46,420 expected in 2014. But in the category of those numbers: aspirin. built against the cancer. Those who began taking it three cut the risk of cardiovascular disease. More recent research estimated deaths, this cancer jumps to fourth, with The population-based study used data collected from years before entering the study reduced their risk by 48 has associated the regular use of aspirin with lowered 39,590 anticipated. The discrepancy underlines pancreatic 362 pancreatic cancer patients diagnosed between January percent. After 10 years of regular use, the risk declined by risk of certain cancers, including colorectal, esophageal, Harvey Risch, MD, PhD cancer’s deadliness. By the time it is diagnosed, treatment 2005 and August 2009 in 30 Connecticut hospitals. It 60 percent. ovarian, and breast. Dr. Risch’s investigation is the first is rarely effective. The five-year survival rate is less than found that patients who habitually took low-dose (75 Dr. Risch also found the reverse correlation: patients who to demonstrate a link between the duration of aspirin use five percent. to 325 milligrams) or regular-dose aspirin significantly stopped taking aspirin within two years of entering the and risk of pancreatic cancer.
12 Yale Cancer Center | Year in Review 20114 yalecancercenter.org | Yale Cancer Center 13 “Anything that cuts the risk of Previous epidemiological studies of aspirin’s effects Risch and the American Cancer Society don’t recommend patient. He is developing a screening process to predict a big difference in terms of outcomes, but advancing surgery on pancreatic cancer have been inconsistent, said Dr. cancer in half is a substantial benefit taking a daily aspirin solely as a preventative against patient’s risk two or three years before diagnosis. by two or three years may help. It’s a way to see if we can Risch, most likely for two intersecting reasons, one to the population.” pancreatic cancer, because of the risks associated with “For instance, the test could determine that you might move the clock back a little.” related to history and the habits of the general public, the long-term use of aspirin, such as gastrointestinal bleeding have a thirteen percent chance of diagnosis within the next Dr. Risch’s collaborators in the study included Samantha other to the nature of the cancer. Thirty years ago, most evaluating aspirin usage and risk.” and stroke. About four or five percent of the general five years,” said Dr. Risch, “and on that basis you could Streicher, a doctoral student in his lab, and Dr. Lingeng people took aspirin for temporary relief of pain, fever, Dr. Risch expected to find an association in the recent population would suffer serious consequences from choose to have a more aggressive workup to see if there’s Lu and Dr. Mark Kidd at Yale Cancer Center, and Dr. or inflammation. That intermittent use made it difficult study, but the results startled him. “Anything that cuts long-term use of aspirin, whereas only 1.5 percent of the anything present. It’s not clear whether this would make a Herbert Yu at the University of Hawaii Cancer Center. to study aspirin’s long-term effects on disease. But in the the risk of cancer in half is a substantial benefit to the population will get pancreatic cancer. So for the general mid-1980s, large numbers of people began taking daily population,” he said. population, the risks outweigh the benefits. low-dose aspirin to prevent cardiovascular disease. This Researchers don’t yet understand how aspirin inhibits Yet Dr. Risch is convinced that daily low-dose aspirin consistent regimen created a population that researchers cancer development. The current theory credits the should be considered by people with family histories could investigate over time. compound’s anti-inflammatory properties. We know that of pancreatic cancer or other cancers and diseases. For That’s exactly what Dr. Risch and other scientists who inflammation stimulates cells to reproduce more frequently, instance, about 10 percent of the general population will study pancreatic cancer needed. “From initial cell damage, which can cause genetic alterations that lead to cancer. get colorectal cancer, and 25 to 30 percent will develop it takes 10 or 11 years for the formation of pancreatic Aspirin might hinder the inflammation and cell-stimulation cardiovascular disease. cancer cells,” explained Dr. Risch, “and it’s usually another that can set off a chain reaction ending in disease. “Aspirin is cheap and well tolerated and seems to reduce five years before the disease is diagnosed. So from the Dr. Risch thinks that other explanations are also worth the risk of a number of cancers,” he said, “so maybe half the initiation of disease to diagnosis can be 15 years. Since the exploring. Aspirin works against cardiovascular disease population would benefit from a daily low-dosage regimen. general population didn’t begin using low-dosage aspirin because of its effects on platelets and blood clotting. “That Each person has to evaluate the risks and benefits, and until the mid-1980s, you wouldn’t expect to see any might be relevant for cancer occurrence,” he said, “if it discuss them with their healthcare provider. Like everything effect on pancreatic cancer until 2000 or 2005 at the works by some mechanism or some other pathway that we else today, it has to be tailored a little carefully.” earliest, which is why we collected data between 2005 haven’t established yet.” Meanwhile Dr. Risch is looking for ways to detect and 2009. We’re now in a much better position to start Despite Dr. Risch’s findings and similar studies, both Dr. pancreatic cancer earlier, before little can be done for the
14 Yale Cancer Center | Year in Review 20114 yalecancercenter.org | Yale Cancer Center 15 Developmental Therapeutics RESEARCH PROGRAM
Tumors, by their very nature, are acidic, Engelman began exploring the idea. cells. “The beauty of pHLIP,” said Dr. Engelman, “is that and the most acidic cancers are also the most aggressive. Meanwhile two other Cancer Center researchers—W. it essentially uses the acidity of the tumor as a biomarker.” A team of scientists at Yale Cancer Center, has developed Mark Saltzman, PhD, Goizueta Foundation Professor The team loaded pHLIP with anti-miR PNAs aimed at a way to use a tumor’s acidity to guide drug therapy and Chair of Biomedical Engineering, and Frank J. switching off signals from miR-155. “It’s like a guided directly into its cells. Slack, PhD, formerly of the Yale Cancer Genetics missile delivering a warhead,” explained Dr. Engelman. Because acidity is common across all tumors, this new and Genomics Program and now at Harvard—were “The missile is guided by acidity, the propulsion system delivery system also outflanks the problem of tumor collaborating on a project. Dr. Slack’s lab had developed a is the pHLIP, which penetrates the defensive system of the heterogeneity, which often allows cancer cells to escape genetically engineered mouse model for lymphoma, and cancer cell, and the PNA is the warhead.” therapies aimed at a specific biomarker. But cancer Dr. Saltzman’s lab had designed technology capable of When they tested this weapon on Dr. Slack’s mice, the can’t escape its basic acidic metabolism. “The only way delivering drugs via nanotechnology. tumors died and metastasis was suppressed. Because the tumor could become resistant,” said Donald M. Which leads to another key collaborator: Peter M. the weapon attacked only cancer cells, side effects on Donald M. Engleman, PhD Engelman, PhD, Eugene Higgins Professor of Molecular Glazer, MD, PhD, Robert E. Hunter Professor and Chair surrounding cells were minimal. The team took a video of Biophysics and Biochemistry, “is to stop growing, which of Therapeutic Radiology. Dr. Glazer’s lab is expert at a cancerous mouse, unable to move and clearly almost dead. is fine with everybody.” designing and synthesizing analog treatment compounds. Three days after being treated, this same mouse looked The breakthrough demonstrates the multiplier effect Dr. Glazer provided peptide nucleic acids (PNAs) that transformed, ambling around its cage. of combining insights from several disciplines to create Dr. Saltzman loaded onto nanoparticles that targeted “So it was a constellation of research by four labs,” said something revolutionary. Nearly 20 years ago Dr. lymphoma in Dr. Slack’s mice. Early experiments indicated Dr. Engelman. “Each of us contributed expert knowledge Engelman’s lab discovered that a small piece of soluble that the PNAs slowed down the growth of lymphomas by that made the whole enterprise work, and it was all made protein called a pHLIP peptide would spontaneously interfering with the tumor’s microRNAs (miRs). These are possible by the Cancer Center, which funded it and insert itself across a membrane in an acidic environment. small but influential signaling RNAs that shut down tumor brought us together.” “But what I didn’t know until mid-2005 or 2006,” suppressors and thus are critical to the spread of cancer. The Dr. Engelman is excited by the delivery system’s said Dr. Engelman, “was that tumors are acidic.” This principal miR implicated in lymphoma is miR-155. possibilities. Many hundreds of microRNAs have been Turning Cancer’s Metabolism information came from colleagues Dr. Oleg Andreev and This is when Dr. Engelman joined the collaboration. He identified in human cells, and if science can identify their Dr. Yana Reshetnyak, now at the University of Rhode offered a new method of delivery—pHLIP, the peptide functions, he says, “then we could throw switches for all Against Itself Island, who wondered if pHLIP would enter tumors. Dr. whose attraction to acidity allows it to penetrate cancer kinds of purposes, not just for treating cancer.”
14 Yale Cancer Center | Year in Review 2011 yalecancercenter.org | Yale Cancer Center 1517 Cancer Prevention and Control RESEARCH PROGRAM
Electronic cigarettes, which deliver a dose of enticing, especially to youth. They are investigating using e-cigarettes expected to start smoking regular nicotine via vapor instead of smoke, were not introduced whether these flavors change behaviors and perceptions cigarettes within a year. to the marketplace until 2007 but have spread like about the risks of tobacco, and also whether they increase The Yale researchers have found that e-cigarettes are wildfire. Estimated sales of e-cigarettes are on pace to the likelihood of nicotine addiction. not used just by cigarette smokers, but by kids who have grow from $1.7 billion in 2013 to $2.5 billion in 2014. In 2012, Dr. Krishnan-Sarin and her colleagues never smoked a regular cigarette. “Many state that if the More and more young people are among those buying, began collecting information about e-cigarettes in 10 products didn’t have flavors, they would never have tried according to Suchitra Krishnan-Sarin, PhD, Associate Connecticut middle schools and high schools. Through them,” explained Dr. Krishnan-Sarin. E-cigarettes are Professor of Psychiatry and Co-leader of the Yale focus groups and anonymous surveys, the researchers also being advertised on television, which cannot be used Tobacco Center of Regulatory Science (TCORS). The are compiling data about use-rates and why kids are to advertise cigarettes. Yale TCORS, created by a $20 million federal grant in attracted to these products. The manufacturers of e-cigarettes tout them as an 2013, is one of 14 such research centers being funded “We are seeing significant rates of increase in the use of alternative for smokers who want to quit, and as a by the Food and Drug Administration (FDA) and these products by youth,” said Dr. Krishnan-Sarin. In the cleaner form of nicotine delivery, far less toxic than the the National Institutes of Health to study the risks of most recent data, 25 percent of the high school students carcinogenic chemicals in tobacco smoke. Researchers e-cigarettes. had tried e-cigarettes, and 12 percent had used them in are looking into those claims. At the moment, no one knows what is in the vapors that the past month. “That’s substantial,” she said. Among Meanwhile, notes Dr. Krishnan-Sarin, “vaping shops”
Suchitra Krishnan-Sarin, PhD millions of people are pulling into their lungs, what is in middle school students, 3.5 percent had tried e-cigarettes, are offering unregulated electronic products some of their exhalations, or what the effects are on health. None 1.5 percent in the past month. Perhaps equally alarming, which are being shown to deliver much higher nicotine of this is regulated because there is not enough research among those who had not yet tried e-cigarettes, 32 levels than a regular cigarette. “We know so little about available to base regulations on. “To get to that point we percent of high schoolers and 26 percent of middle e-cigarettes,” she said, “and there’s this increase in use- need sufficient scientific evidence,” said Dr. Krishnan- schoolers said they might try them in the future. rates among youth, which is very concerning because you Sarin, “and we don’t have it yet.” This echoes the findings of the latest National Youth may be creating a generation that is addicted to nicotine. Yale’s TCORS is focused on the role played by flavors Tobacco Survey by the Centers for Disease Control and Will they then move on to regular cigarettes?” The Growing Use Of such as menthol, cherry, and chocolate that are added Prevention, which found that the number of youths It will be another few years, she added, before the FDA to the tobacco in e-cigarettes. The Center’s scientists who had never smoked but had used e-cigarettes nearly has enough scientific evidence from Yale and the other E-Cigarettes Among Youth are studying whether flavors make e-cigarettes more tripled between 2011 and 2013. Worse, half of the kids Tobacco Centers to consider writing regulations.
22 Yale Cancer Center | Year in Review 2011 yalecancercenter.org | Yale Cancer Center 1923 Cancer Immunology RESEARCH PROGRAM
As a waste by-product of tumor metabolism, prognosis, which suggests that tumors somehow recruit molecules, and finally to the surprising source within the lactic acid has largely been overlooked by cancer macrophages and corrupt their normal function as tumor tumor: lactic acid. Experiments in mouse models led to the scientists. New research at Yale Cancer Center, however, suppressors, turning them into promoters of cancer. Dr. insight that knocking out Arg1 diminished tumor size. demonstrates that this common chemical compound, Colegio and his colleagues set out to find the signals that For Dr. Colegio, all of this links to his clinical work caring produced by the rapid division of neoplastic cells, instructed macrophages to become cancer’s allies. for recipients of solid organ transplants. To prevent rejection transforms immune cells called macrophages into abettors “The recruited macrophages act as if there’s a wound of the transplanted organ, these patients must take strong of tumor growth. The researchers also identified an that won’t heal or a tissue that’s stressed,” explained Dr. immuno-suppressant drugs, but the drugs cause a one enzyme within tumor-associated macrophages (TAMs) Colegio, “so they produce growth factors and vascularize hundred-fold increased risk of numerous, aggressive skin that plays a critical role in promoting tumor development. the tumor to restore homeostasis. But that can’t happen cancers, mostly squamous cell carcinoma. That’s what led Further, they discovered that removing this single enzyme, in neoplasia, so the macrophage ends up feeding the Dr. Colegio to study tumor-activated macrophages. called arginase 1 (ARG1), from a macrophage decreased tumor’s growth.” He’s now analyzing fresh skin cancers taken from the size of tumors by half. The research team learned that macrophages are recruited patients, and has found that even in very early stages of “That speaks to the important role of macrophages in early in the tumor’s development. Through a series of in skin cancer, the number and density of macrophages is the tumor progression,” said Oscar R. Colegio, MD, PhD, vitro experiments on macrophages, the scientists detected same as in the later invasive phases. “So we suspect that Assistant Professor of Dermatology. “They make up only two proteins critical for tumor growth: a signaling protein macrophages help to coordinate the invasion process,” Oscar R. Colegio, MD, PhD one to five percent of the cells in our tumor models, yet called vascular endothelial growth factor (VEGF), and the said Dr. Colegio, “and if they play a role in that, this may eliminating one enzyme from that cell type reduces tumor enzyme arginase 1 (ARG1). Further research revealed that be a target that has not yet been exploited in anti-cancer size significantly.” these two proteins used a signaling pathway mediated by a therapies, or in early cancers to try to prevent progression. The research took seven years. Dr. Colegio’s postdoctoral transcription factor called HIF1A (hypoxia-inducible factor We could target either the macrophages or use an arginase research mentor and now main partner throughout the 1-alpha). The signals and proteins functioned to convince inhibitor to knock out the enzymatic function that’s vital investigation is Ruslan M. Medzhitov, PhD, David W. the macrophages that they were in a state of hypoxia, to tumor progression.” Wallace Professor of Immunobiology and Investigator of stimulating the macrophages into furious activity that Dr. Colegio is excited by the wider implications of his the Howard Hughes Medical Institute. At the beginning, helped the tumor grow. team’s findings. The principles, he said, “will likely hold they knew that macrophages are found in all tumors, and At that point, they still didn’t know the primary activator. true not just specifically for one cancer type but more that the more of them a tumor contains, the worse the More investigation took them beyond proteins into broadly across any proliferating tissue.” How Immune Cells Go Rogue
2018 Yale Cancer Center | Year in Review 20141 yalecancercenter.org | Yale Cancer Center 19 Molecular Virology RESEARCH PROGRAM
Most people think of cancer and HIV as diseases quickly weakens the immune system, opening the door to constantly and changes its shape. This protean quality with little in common. But the two are strongly connected, cancer viruses such as Kaposi sarcoma-associated human has defeated all attempts to formulate a vaccine. Now Dr. said Daniel DiMaio, MD, PhD, Waldemar Von Zedtwitz herpes virus-8 (HHV8), Epstein-Barr virus, and human Mothes and others have used electron microscopy to look Professor of Genetics and Deputy Director of Yale Cancer papillomavirus. Second, even people whose HIV infection deep into HIV and watch in real time as the virus changes Center. “That’s why HIV studies have always been an is controlled with antiretroviral therapy are more shape and attacks cells. important part of our portfolio at the Cancer Center.” susceptible to cancer than the general population because The researchers saw how the virus infects: a surface So it can be frustrating when asked why a cancer center their immune system remains compromised by the spike protein penetrates a healthy cell and fuses with it. is studying HIV. “It’s mostly a matter of educating infection. Unsurprisingly, they have a higher incidence of To escape detection, this protein stays closed as much people,” explained Dr. DiMaio. cancers typical of AIDS, such as Kaposi sarcoma, but HIV as possible, opening only briefly to change shape and That begins by understanding that HIV is a virus, and also seems to amplify the activity of other virus-induced infiltrate another cell. “To infect a cell,” described Dr. that some viruses cause cancer. Viruses cause about cancers, including anal, liver, and cervical cancers. Mothes, “the virus needs to open up.” Walther Mothes, PhD 15 percent of all cancers. Hepatitis B and C viruses “Cancer remains a leading cause of death among AIDS If researchers can devise a drug that keeps the spike account for most of the world’s liver cancer. The human patients,” said Dr. Mothes. protein closed, the virus can’t infect. Scientists have papillomavirus accounts for all of the world’s cervical A possible third connection between HIV and cancer is discovered that some AIDS patients have developed cancer and approximately 30% of head and neck cancers also emerging. In HIV-infected patients who have been “broadly neutralizing antibodies” that offer protection in the United States. Though a direct link between HIV on antiretroviral therapy for many years, researchers against the disease, but no one knew how the antibodies and cancer hasn’t yet been found, researchers have started are finding indications that the virus integrates into work. It now appears as if these antibodies block infection to suspect that one exists. chromosomal DNA and causes clonal expansion of by locking the spike protein in the closed position. The indirect links between HIV and cancer are well T-cells. “That’s a precursor to the development of This gives researchers a target for a vaccine. “It’s a major established. “There are at least three connections,” said cancer,” explained Dr. Mothes. There’s a possibility advance,” said Dr. Mothes. “If we can generate a vaccine Walther Mothes, PhD, Associate Professor of Microbial that over time, in addition to HIV’s indirect role as an to protect the population against HIV, and if patients no Pathogenesis and newly appointed Co-Director of the immunosuppressant, the virus may become recognized as longer have to take antiretroviral medications, we would Cancer Center’s Molecular Virology program, who a direct carcinogen. also relieve many people from the burden of cancer. That The Links Between studies HIV. All of this is why new research has excited HIV scientists. is one reason that it is important for a cancer center to First, notes Dr. Mothes, if HIV is left untreated, AIDS To elude attack by the immune system, the virus mutates include the study of HIV.” HIV And Cancer
2022 Yale Cancer Center | Year in Review 20114 yalecancercenter.org | Yale Cancer Center 21 Cancer Genetics and Genomics RESEARCH PROGRAM
From a cancer cell’s point of view, metastasis is metastasis is suppressed. That suggests that RBP2 is a good developing those compounds so that we can use them in a risky, complicated migration. First the cell must escape candidate for a targeted cancer therapy against metastasis.” the clinic,” said Dr. Yan. the primary tumor and launch itself into the bloodstream. This is an exciting breakthrough, since breast cancer Some of that work is being done through the National Then it must find a way to exit this flow and establish itself strikes more women than any other cancer and is Cancer Institute’s Experimental Therapeutics Program, on the shores of a distant organ. Finally it must develop particularly adept at aggressive metastasis, usually to the called NExT, which aims to advance breakthrough the means to multiply and colonize a hostile foreign lungs, bones, or brain. Once this cancer metastasizes, the discoveries in the laboratory into new therapies for
environment. Every stage is fraught with physiological options for treatment dwindle, along with survival rates. cancer patients. Dr. Yan’s team is taking a three-pronged Qin Yan, PhD hazards and requires a knack for adapting to new conditions. Tracking down RBP2 (also known as JARID1A or approach. The first prong is using traditional medicinal Scientists have long been curious about how cancer cells KDM5A) and deciphering its function took Dr. Yan and chemistry, to search for derivatives of the inhibitory survive their metastatic journey. The cells don’t change his colleagues three years. First they used gene expression compounds that are more potent and specific. The their essential genetic nature, which is why breast cancer datasets of breast cancer patients to identify RBP2 as a second is an expansion of the initial molecular screening cells, for example, are recognizable wherever they land after recognized regulator of metastasis. Then they did global from 10,000 molecules to 100,000, again with the goal of metastasis. Rather, the cells rely on reversible modifications genome-wide profiling to determine which genes were finding stronger, more specific compounds. The third in gene expression through epigenetic changes, using regulated by RBP2 and to confirm its importance. Next approach involves computational-based drug design for enzymes that help them stay alive while moving from one they completed cell-based assays, which confirmed that inhibitors of RBP2. environment to the next. But which enzymes? And how RBP2 expression is critical in breast cancer tumorigenesis “We have already identified some better compounds,” do those enzymes function in metastasis? Identifying these and metastasis. Lastly they tested these findings in two said Dr. Yan, “but in a year or so we hope to have much regulators of gene expression is the necessary first step to mouse models, one of which required them to use a more potent ones.” He and his colleagues will test the new stop the migration of cancer cells. genetically engineered mouse model that Dr. Yan created. compounds first in biochemistry assays, then in cells, then A team at Yale Cancer Center led by Qin Yan, PhD, Experiments in the mouse models validated their findings in mice. If all goes well, the next stage would be a clinical Associate Professor of Pathology, has discovered a derived from the clinical datasets. trial. Dr. Yan expects to see that in about three years. regulating enzyme called RBP2 that breast cancer cells Dr. Yan and his colleagues also began screening Our hope is to take what we know from the clinic and need in order to metastasize to the lung. “We found small molecules to look for inhibitors of RBP2. They run it through the experimental system, and after we know Blocking Metastasis In that not only is this enzyme implicated in metastasis,” identified some first-in-class compounds that modulate the mechanism and the inhibitors, we bring it back into explained Dr. Yan, “but also that if you suppress it, or suppress the enzyme’s activity. “We are further the clinic, so we are learning in both directions.” Breast Cancer 16 Yale Cancer Center | Year in Review 2011 yalecancercenter.org | Yale Cancer Center 17 24 Yale Cancer Center | Year in Review 2014 Radiobiology and Radiotherapy RESEARCH PROGRAM
The DNA in the nuclei of our cells gets tattered to DNA double-strand breaks. These physical breaks in cells isolated from human patients, they can then treat every day from forces within, such as free radical damage, the DNA helix are healed by BRCA2 through a complex the cells in tissue culture with various chemotherapy and also from without, such as the sun’s UV rays. The process called homologous recombination. But if the drugs, and study the cellular response of the BRCA2 result is an estimated 20,000 DNA lesions per cell each day. breaks aren’t repaired properly, you get mutations in the gene. Most of the drugs cause DNA damage. Dr. Jensen The body’s DNA repair system is superb at fixing these, but genes that drive the cancer process.” wants to know what happens when BRCA2 is depleted no system is perfect. If defective DNA is left unmended, it One reason for the mystery is that scientists didn’t from a breast or ovarian cell. “Does it instantly become can cause cellular mutations that lead to cancer. understand BRCA2 biochemistry. To study it would genomically unstable? Does it die? If it doesn’t die, how Ryan B. Jensen, PhD, Assistant Professor of Therapeutic require, for starters, purifying the protein coded for by the does it survive? Does it become a tumor cell? Those are Radiology and Pathology, is unraveling the connections BRCA2 gene. But the BRCA2 protein is large, unstable, the genetic questions we’re trying to address.” between DNA repair, breast cancer, and ovarian cancer. and fragile, all obstacles to purifying it. Dr. Jensen and his Once Dr. Jensen and his colleagues have the biochemical His lab is looking for the instigating molecular events that colleagues worked on the problem for several years, and and genetic answers, drug-makers will have targets for new trigger mutations by tracing their origins to the BRCA2 in 2010 became the first to succeed at purifying the entire therapies against breast and ovarian cancer. And perhaps (Breast Cancer Susceptibility) gene. It is well established BRCA2 protein. Using the same process, they are now other cancers as well. that women who inherit a mutation in BRCA2 are at purifying mutant forms of BRCA2 taken from patients. “A failure in DNA repair,” explained Dr. Jensen, “ is Ryan B. Jensen, PhD high risk of developing breast and ovarian cancer. Without That allowed the researchers to study the proteins probably the driving force behind all mutations that the BRCA2 mutation, for instance, women have a 12 without all the interfering noise within cells. They put arise in cancer. DNA damage is an ever-present danger, percent chance of getting breast cancer; with the mutation, the purified proteins—normal and mutant—into test and if these DNA repair genes are not working properly, the risk jumps to 90 percent over a patient’s lifetime. tubes or in vitro assays, mixed them with broken pieces you’re getting more genomic instability and mutations. What’s unclear is why BRCA2 mutations strike the of DNA, and watched how they handled repair or failed DNA repair genes are in charge of this process. If we can The Interconnected Mysteries breast and ovaries. to. The goal is to pinpoint how and why something goes understand that process, we can develop new therapeutic “No one has a clue why that is,” said Dr. Jensen, “why wrong when BRCA2 is mutated, and why this defect leads avenues for treating cancer.” it’s not the lungs or the brain. That’s a big mystery. My cells down the path towards tumorigenesis in the breast If we know that, a patient could come in and get Of DNA Repair And lab is doing basic research to understand the biology of or ovaries. the sequencing done, and then get the drugs that are what BRCA2 does, and what happens when it can’t do In addition to the biochemical research, Dr. Jensen’s lab most effective.” Breast Cancer its job. BRCA2 is a DNA repair protein that responds is studying BRCA2 genetics. Using breast and ovarian
24 Yale Cancer Center | Year in Review 2011 yalecancercenter.org | Yale Cancer Center 2527 Signal Transduction RESEARCH PROGRAM
Melanoma ranks among the most lethal common miRNAs upregulated by the BRAF and NRAS Notch already exist, and these can be tested against cancers, causing about 80 percent of all skin cancer oncogenes. They identified the miRNA with the most melanoma cells. Unfortunately these older Notch deaths. Scientists have traced most melanomas—nearly elevated levels: miR-146a. But their work was just beginning. inhibitors have strong gastrointestinal side effects. 70 percent of them—to mutations in the BRAF and They began studying miR-146a’s downstream effects “But the new Notch antibodies are highly specific,” NRAS genes. But what happens in the interval between on signaling pathways that lead to melanoma. They said Dr. Wajapeyee, “blocking only specific forms of the onset of these mutations and the proliferation of learned that miR-146a targets a protein called NUMB and Notch that are pro-oncogenic. They are highly effective melanoma cells? What signals and mechanisms set off the suppresses it. NUMB ordinarily regulates Notch, a receptor and do not produce any GI-tract problems.” He and his cascade of responses that ends in skin cancer? pathway favored by cancer. So when NUMB is suppressed team, in initial testing on cell lines, found that the most The answers to these questions, once unclear, have and miR-146a begins overexpressing, the signals from effective treatment against melanoma was a combination recently been answered by findings at Yale Cancer Notch, now unregulated, get amplified. This prompts even of drugs that inhibited both the production of Center. Narendra Wajapeyee, PhD, Assistant Professor heavier production of miR-146a, inducing skin cancer cells miR-146a and the Notch signaling pathway. He also of Pathology, and his team have traced the connections. to proliferate and grow faster. Result: melanoma. foresees possibilities in combining these targeted therapies BRAF and NRAS cannot form tumors without the Next Dr. Wajapeyee and his team theorized that with immunotherapies. crucial contribution of a microRNA called miR-146a. suppressing miR-146a would interfere with Notch Among all cancer types, he noted, melanoma has the The discovery, noted Dr. Wajapeyee, reveals one of signaling and disrupt the progression toward melanoma. highest number of mutations on its genome. “For that Narendra Wajapeyee, PhD melanoma’s vulnerabilities and gives drug developers an Without help from miR-146a, Notch signaling was reason, the melanoma cells will find ways to escape most obvious target. “They can test approaches against miR- silenced and the melanoma cells stopped growing. “We therapies. So it may be best to combine two or three 146a,” he said, “to see whether we can effectively cure found that miR-146a is required for BRAF and NRAS approaches and kill them early on before they evolve. metastatic melanoma.” transformation,” explained Dr.Wajapeyee, “and that they Dr. Wajapeyee and his team are now using genomics Previous research has established that microRNAs cannot form tumors without it.” and screening to identify a new target: the genes that (miRNAs) regulate gene expression and play a part in The findings suggest a clear method of fighting allow melanoma cells to survive while circulating tumorigenesis and metastasis, but the miRNA activator melanoma: knock down production of miR-146a to stop in the bloodstream after the primary tumor in melanoma was unknown. Dr. Wajapeyee and his team it from blocking NUMB and activating Notch signaling, metastasizes. “If we can intercept these cells,” said Dr. Silencing The Signals That Lead worked for almost five years to reach their breakthrough. or target the Notch pathway itself. Dr. Wajapeyee noted Wajapeyee, “we can make them die in the bloodstream They began by analyzing melanomas to find the most that pharmacological antibodies that specifically inhibit and prevent metastasis.” To Melanoma
2628 Yale Cancer Center | Year in Review 20114 yalecancercenter.org | Yale Cancer Center 27 Yale Cancer Center Leadership
Yale Cancer Center Yale Cancer Center Research Programs Yale Cancer Center Shared Resources Smilow Cancer Hospital at Yale-New Haven Smilow Cancer Hospital Clinical Programs
Thomas J. Lynch, Jr., MD Cancer Genetics and Genomics Biostatistics Thomas J. Lynch, Jr., MD Brain Tumor Pediatric Oncology and Hematology Director Marcus W. Bosenberg, MD, PhD Xiaopan Yao, PhD Physician-in-Chief Clinical Program Leader: Clinical Program and Translational Working Group Leader: Lajos Pusztai, MD, DPhil Joachim M. Baehring, MD Gary Kupfer, MD Daniel C. DiMaio, MD, PhD Cesium Irradiator Abe Lopman Translational Working Group Leader: Deputy Director Cancer Immunology Ravinder Nath, PhD Senior Vice President, Operations Kevin P. Becker, MD, PhD Phase I Lieping Chen, MD, PhD Executive Director Clinical Program Leader and Translational Kevin Vest, MBA, FACHE Madhav V. Dhodapkar, MBBS Clinical Research Services Breast Cancer Working Group Leader: Deputy Director, Finance and Administration Howard S. Hochster, MD Rogerio C. Lilenbaum, MD Clinical Program Leader: Joseph Paul Eder, MD Cancer Prevention and Control Chief Medical Officer Anees B. Chagpar, MD Roy S. Herbst, MD, PhD Melinda L. Irwin, PhD Flow Cytometry Translational Working Group Leader: Prostate and Urologic Cancers Associate Director, Translational Science Yong Zhu, PhD Ann Haberman, PhD Catherine Lyons, RN, MS Lajos Pusztai, MD, DPhil Clinical Program Leader: Executive Director, Smilow Patient Care Services Peter G. Schulam, MD, PhD Howard S. Hochster, MD Developmental Therapeutics Pathology Tissue Services Endocrine Cancers Translational Working Group Leader: Associate Director, Clinical Sciences Karen S. Anderson, PhD David Rimm, MD, PhD Kerin B. Adelson, MD Clinical Program and Translational Working Group Leader: Daniel P. Petrylak, MD Barbara A. Burtness, MD Chief Quality Officer Tobias Carling, MD, PhD Melinda L. Irwin, PhD Rapid Case Ascertainment Deputy Chief Medical Officer Sarcoma Associate Director, Population Sciences Molecular Virology Rajni Mehta, MPH Gastrointestinal Cancers Clinical Program Leader: Walther H. Mothes, PhD Michael D. Loftus Clinical Program and Translational Working Group Leader: Gary E. Friedlaender, MD Patricia M. LoRusso, DO Wendell G. Yarbrough, MD Yale Center for Genome Analysis Vice President, Financial Operations Howard S. Hochster, MD Translational Working Group Leader: Associate Director, Innovative Medicine Shrikant Mane, PhD Dieter M. Lindskog, MD Radiobiology and Radiotherapy Arthur Lemay Gynecologic Cancers David F. Stern, PhD Peter M. Glazer, MD, PhD Yale Center for Molecular Discovery Executive Director, Smilow Cancer Network Clinical Program Leader: Therapeutic Radiology Associate Director, Shared Resources Joann B. Sweasy, PhD Craig Crews, PhD Peter Schwartz, MD Clinical Program Leader: Anne Chiang, MD, PhD Translational Working Group Leader: Lynn D. Wilson, MD, MPH Anees B. Chagpar, MD Signal Transduction Chief Network Officer Alessandro D. Santin, MD Translational Working Group Leader: Assistant Director, Diversity and Health Equity Daniel P. Petrylak, MD Deputy Chief Medical Officer Roy H. Decker, MD, PhD David F. Stern, PhD Head and Neck Cancer Peter G. Schulam, MD, PhD Clinical Program Leader: Thoracic Oncology Assistant Director, Surgery Wendell G. Yarbrough, MD Clinical Program Leader: Translational Working Group Leader: Frank C. Detterbeck, MD Gary Kupfer, MD Barbara A. Burtness, MD Translational Working Group Leader: Assistant Director, Pediatrics Roy S. Herbst, MD, PhD Hematology Ruth McCorkle, RN, PhD Clinical Program Leader: Assistant Director, Psychosocial Oncology Steven D. Gore, MD gi v e Be part of our mission to bring the world Closer to Free. Translational Working Group Leader: Jeffrey Sklar, MD, PhD closer tofree Madhav V. Dhodapkar, MD, PhD Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven have joined forces to create Closer to Free, a fund that Assistant Director, Pathology & Tissue provides essential financial support for breakthrough cancer research and compassionate patient care by combining the gifts of Acquisition Services many donors. Your contribution is critical to ensure that new research can be pursued without delay, promising treatments are Melanoma aggressively developed, and patient care is continuously enhanced. Clinical Program Leader: Edward Snyder, MD Stephan Ariyan, MD Assistant Director, Membership Learn More >> www.giveclosertofree.org Translational Working Group Leader: Harriet Kluger, MD
30 Yale Cancer Center | Year in Review 2014 yalecancercenter.org | Yale Cancer Center 31 Yale Cancer Center Membership
Cancer Genetics and Genomics Cancer Immunology Cancer Prevention and Control Developmental Therapeutics Molecular Virology Radiology and Radiotherapy Signal Transduction
Allen Everett Bale Rossitza Lazova Stephan Ariyan Kerin Bess Adelson Asher Michael Marks Maysa Mahmoud Abu-Khalaf Harriet M. Kluger Janet L. Brandsma Ranjit S. Bindra Anton M. Bennett Linda M. Bartoshuk David J. Leffell Philip William Askenase Steven L. Bernstein Susan T. Mayne Karen S. Anderson Jaseok Koo Daniel C. DiMaio Daniel J. Boffa Titus Boggon Susan J. Baserga Peter Lengyel Kevin Patrick Becker Elizabeth H. Bradley Ruth McCorkle Masoud Azodi Jill Lacy Ayman Sayed El-Guindy Douglas E. Brash David A. Calderwood Lauren Paige Blair Peining Li Jeffrey R. Bender Brenda Cartmel Sherry McKee Joachim M. Baehring Jia Li Andrew Goodman David Joel Carlson Lloyd Garnet Cantley Jean L. Bolognia Richard P. Lifton Alfred L. M. Bothwell Anees B. Chagpar Rajni Lynn Mehta Debra Schwab Brandt Rogerio C. Lilenbaum Stanley David Hudnall Richard E. Carson Toby C. Chai Marcus W. Bosenberg Haifan Lin Richard Bucala Elizabeth Brooks Claus Sarah Schellhorn Mougalian Ronald R. Breaker Dieter M. 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Risch Jennifer Nam Choi Jennifer Moliterno Brett D. Lindenbach Roy H. Decker Jaime Grutzendler Bernard G. Forget James P. Noonan Kavita Dhodapkar Cary P. Gross Peter Salovey Gina G. Chung Gil G. Mor Robert E. Means Jun Deng Mark W. Hochstrasser Alan Garen Manoj Pillai Madhav V. Dhodapkar Theodore R. Holford Tara Sanft Jason Michael Crawford Natalia Neparidze I. George Miller Francesco DErrico Valerie Horsley Mark B. Gerstein Manju Prasad Richard L. Edelson Melinda Liggett Irwin Dena J. Schulman-Green Craig M. Crews Terri Lynn Parker Kathryn Miller-Jensen Frank C. Detterbeck Michael E. Hurwitz Antonio J. Giraldez Lajos Pusztai Brinda Emu Beth A. Jones Dave Sells Henk De Feyter Pasquale Patrizio Walther H. Mothes James S. Duncan Karl L. Insogna Murat Gunel Peter E. Schwartz Richard A. Flavell Nina S. Kadan-Lottick Fatma M. Shebl Hari Anant Deshpande Peter Natale Peduzzi Anna Marie Pyle Suzanne B. Evans Richard Glenn Kibbey Shangqin Guo Emre U. Seli Francine M. Foss Jennifer M. 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Hoh Scott Donald Weatherbee Paula B. Kavathas Steven B. Leder Yawei Zhang Leonard Raymond Farber Thomas J. Rutherford Peter John Tattersall Fahmeed Hyder Wang Min Natalia B. Ivanova Sherman Morton Weissman Steven H. Kleinstein Haiqun Lin Tongzhang Zheng James J. Farrell W. Mark Saltzman Anthony N. Van den Pol Ryan B. Jensen Jon Stanley Morrow Samuel G. Katz Andrew Zhuo Xiao Mark Joseph Mamula Shuangge Steven Ma Yong Zhu Scott Nicholas Gettinger Alan Clayton Sartorelli Yong Xiong Megan C. King Michael H. Nathanson Sajid A. Khan Mina LuQing Xu Jennifer Madison McNiff Xiaomei Ma Sarah B. Goldberg Clarence Takashi Sasaki Wendell Gray Yarbrough Gary Kupfer Don X. Nguyen Kenneth Kay Kidd Tian Xu Ruslan M. Medzhitov Steven D. Gore Alanna Schepartz Wu Liu Daniel Petrylak Yuval Kluger Qin Yan Eric R. F. Meffre Ya Ha William C. Sessa K. Brooks Low Katerina Politi William H. Konigsberg Hongyu Zhao Deepak Narayan Dale Han Brian Matthew Shuch Sheida Mani David L. Rimm Diane S. Krause Joao P. Pereira Roy S. Herbst David Adam Spiegel Meena Savur Moran Joseph Schlessinger Jordan Stuart Pober Seth B. Herzon Preston Sprenkle Evan Daniel Morris Mark J. Solomon Carla Vanina Rothlin Howard S. Hochster Stacey M. Stein Ravinder Nath David F. Stern Nancy Hartman Ruddle Michael Edwin Hodsdon Seyedtaghi (Shervin) Takyar Abhijit A. Patel Derek K. Toomre David G. Schatz Nina Ruth Horowitz Vasilis Vasiliou Richard E. Peschel Benjamin E. Turk Stuart Evan Seropian Sven-Eric Jordt Jiangbing Zhou Kenneth B. Roberts Narendra Wajapeyee Warren D. Shlomchik William L. Jorgensen Faye A. Rogers Robert Martin Weiss Brian Richard Smith Juliane M. Juergensmeier Peter Schulam Kenneth R. Williams Edward Leonard Snyder Patrick A. Kenney Yung H. Son Dan Wu Mario Sznol Patrick Sung John Joseph Wysolmerski Robert E. Tigelaar Joann Balazs Sweasy Xiaoyong Yang Lynn D. Wilson Sandra L. Wolin James Byunghoon Yu Zhong Yun
32 Yale Cancer Center | Year in Review 2014 33 yalecancercenter.org | Yale Cancer Center