“On behalf of SPAEN, our member organizations and all GIST- and Sarcoma patients, we congratulate Prof. Demetri on this so well-deserved award. We thank Dr. Demetri for his tireless research efforts in a rare group of diseases such as GIST and Sarcomas. Thanks also for his continued support to our patients and his engaged collaboration with patient organizations across national borders.”
Markus Wartenberg, Chair/President of SPAEN Sarcoma Patients EuroNet Assoc.
April 29, 2020 George D. Demetri, MD, professor of medicine and co-director of the Ludwig Center at Harvard Medical School, has been named the 2020 David A. Karnofsky Memorial Award recipient for pioneering the development of targeted kinase inhibitors (including imatinib, sunitinib, and regorafenib) for gastrointestinal stromal tumors (GISTs) and for his role in the development of several other therapies for sarcomas. In an interview with ASCO Daily News, he reflected on his early beginnings in oncology, current research interests, and some remaining challenges in the field.
ASCO Daily News: What does this recognition from ASCO mean to you?
Dr. Demetri: It is so important for ASCO to recognize the importance of effective research in rare diseases, such as GISTs; this means the world to me and to patients globally who have benefitted from this work. I am honored, yet humbled, to have been part of these academic and industrial teams that have translated basic science into highly effective therapies for patients in need. I guess I feel a bit guilty for being singled out, because so many other people have contributed to this work, and the credit really goes to many teams around the world. For me, it's an opportunity to say thank you to our field, our patients and our collaborators.
ASCO Daily News: Which events/mentors have fueled your early interests in oncology?
Dr. Demetri: As a child in the 1960s and early 1970s, I always had somebody in the family being treated for cancer, and the physicians of the time could never really explain the disease to me. I became interested in scientific medicine, because the tools of biochemistry and molecular genetics allowed us to understand cancer much better.
So many mentors impacted my career at every step of my training: from the giants at Stanford School of Medicine in the early 1980s (Henry Kaplan, MD; Saul Rosenberg, MD; Ron Levy, MD; Bert Glader, MD; and Irv Weissman, MD), to the remarkable Don Thomas, MD; Fred Appelbaum, MD; and Phil Greenberg, MD, and the entire team at the Fred Hutchinson Cancer Research Center in Seattle during my residency training who encouraged my colleagues and me to ask questions, follow our curiosity, and question authority.
At Dana-Farber Cancer Institute, my mentor was Jim Griffin, MD, who was studying the molecular mechanisms of recombinant human hematopoietic growth factors (HGFs) when they were first being tested as supportive care for patients with cancer. It was inspiring to see how the science of stem cells and cell differentiation could translate directly into improving outcomes for patients through this novel supportive care. Finally, I was fortunate to learn much from Lloyd Old, MD, and Calle Heldin, PhD, of Ludwig Institute for Cancer Research, and Yossi Schlessinger, PhD, of Yale School of Medicine and the companies he founded, including Sugen and Plexxikon.
ASCO Daily News: How did you get involved in sarcoma research?
Dr. Demetri: I got into sarcomas because this was one of the few solid tumors where higher-dose chemotherapy was posited to make a significant difference for patients...that’s about all we had to work with in the 1980s—we had dose, higher dose, and even higher dose. But after about 10 years, as data evolved in most cancers, the fascination with dose intensification wore off, and I was looking for other rational approaches to improving clinical outcomes for patients.
Right around that time, some early clues emerged in sarcomas, demonstrating that many exhibited genetic abnormalities, especially translocations, that were unique to cancer cells; for example, the EWS-FLI1 translocation in Ewing Sarcoma, the translocations involving X and 18 chromosomes in synovial sarcomas, and much later, of course, the KIT mutations in GISTs. Visiting Japanese scholars from Dr. Griffin’s lab learned molecular techniques in his lab and returned to Osaka where they did some of the groundbreaking molecular biology that identified the KIT mutation as a driver in human GISTs.
At the time, my friend Brian Druker, MD, whose lab was one floor down from ours before he moved to Oregon, was developing a small molecule to treat chronic myeloid leukemia by inhibiting the Bcr-Abl tyrosine kinase. He was also an incredible help, role model, collaborator, and unbelievably generous person in terms of connecting me to Novartis and helping us to move forward with some of the earliest work that led to the success of imatinib as the first targeted therapy for GIST.
ASCO Daily News: What is your current research focus?
Dr. Demetri: My work is focused on understanding and overcoming the mechanisms of resistance to kinase inhibitors and a variety of other anticancer therapies in GISTs and other sarcomas, ideally, with extrapolation to other malignancies. With my colleague Joan Brugge, PhD, co-director of the Ludwig Center at Harvard Medical School, we are facilitating collaborations across a universe of investigators throughout Harvard, Dana-Farber, and our affiliated hospitals to tackle this dauntingly complex topic. We’re thinking a lot about what orthogonal approaches we can identify in terms of different structures and different pathways, that could be inhibited safely with non–cross-resistance, to extinguish the very last cancer cell and develop strategies for durable benefits and even cures.
I would say that our research is broad-ranging and opportunistic—if we identify a scientific theme or technology that has high potential to translate into clinical benefit, we will apply it to some of the uniquely predictive sarcoma models and rapidly move into early translational clinical trials to carefully assess the signals of impact on cancers in our patients.
ASCO Daily News: Which challenges remain in the field of connective tissue oncology?
Dr. Demetri: I don’t think that they’re any different than the main challenges in oncology in general—identifying patients who have curative options so that they can be managed by multidisciplinary experts with experience and evidence. We have an opportunity to learn important pan-cancer lessons from rare diseases like sarcomas, which provide important clues to cancer pathogenesis, prognosis, treatment, and even prevention. Mobilizing international collaborations with high-quality data is also key in this information age. ASCO says it well in the tag line that we should learn from every patient.
Fundamentally, our comprehensive cancer center model in the United States allows us to engage with discovery-driven basic scientists and collaborate with our clinical scientist-investigators and clinical experts to identify and predict how tumor cells stay alive, despite any kind of onslaught of drugs and/or radiation therapy. We need research to identify much more clearly what signals drive the cancer cells to resist death, so that we can block those pathways and activate our natural host defense mechanisms while keeping normal cells and tissues healthy.
Source: https://dailynews.ascopubs.org by Jasenka Piljac Žegarac, PhD