Dana-Farber Cancer Institute Boston, Massachusetts
Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School Affiliate Member, Broad Institute Investigator, Howard Hughes Medical Institute
Identifying novel treatment strategies to block estrogen-driven breast cancers.
Most breast cancers require estrogen to grow. Drugs such as fulvestrant, tamoxifen, and aromatase inhibitors block estrogen-driven growth and are effective treatments for estrogen-receptor (ER)-positive breast cancers. Fulvestrant is unique in that it acts by degrading the estrogen receptor on cancer cells. The mechanism by which fulvestrant does this has been a longstanding mystery that Dr. Kaelin is focused on solving. As part of this work Dr. Kaelin’s team is seeking novel drugs that will degrade otherwise “undruggable” proteins that drive breast cancer growth. Leveraging their recent discoveries related to kidney cancer (a cancer that is highly responsive to immunotherapy), Dr. Kaelin’s team is also conducting studies to identify strategies to make breast cancers more easily recognized by the immune system. Collectively, these studies will provide new insights into the action of agents like fulvestrant that may be applicable to other target proteins and ways to improve response to immunotherapy in breast cancer—insights that will ultimately inform the development of better therapies to treat ER-positive breast cancer.
Dr. Kaelin has successfully identified other fulvestrant-like agents and is evaluating the mechanism by which they destroy the estrogen receptor. He and his colleagues have determined that two other proteins, GATA3 and FOXA1, that are required by ER-mediated cell growth may be potential targets for fulvestrant-like agents. In other studies, Dr. Kaelin and his team are examining the targets of CDK4/6 inhibitors which are the mainstays of treatment for hormone receptor-positive breast cancer. Using state-of-the-art methods, they have identified two new proteins that are regulated by CDK4 and CDK6, both of which play important roles in cell cycle growth and repair of damaged DNA.
Dr. Kaelin and his colleagues will build on their findings from several avenues of investigation. They will continue their studies of CDK4/6 inhibition and other CDK4/6 targets that may affect the safety and efficacy of CDK4/6 inhibitors in the clinic. The team will continue screening the new fulvestrant-like agents and determine their mechanism of action. In particular, Dr. Kaelin will examine their potential use to circumvent resistance to fulvestrant and whether similar agents will be effective against two other drivers of estrogen receptor-positive breast cancer, GATA3 and FOXA1.The results of these lines of investigation will help to develop strategies to make breast cancers more recognizable to the immune system to enhance the use of immunotherapy for these patients.
BCRF support has allowed us to rapidly apply the knowledge we have gained from studying other cancers, which was recognized in 2019 with the Nobel Prize, to breast cancer.
William Kaelin, Jr., MD is the Sidney Farber Professor of Medicine in the Department of Medicine at the Dana-Farber Cancer Institute and the Brigham and Women’s Hospital, Harvard Medical School and a Howard Hughes Medical Institute investigator since 1998. He obtained his undergraduate and MD degrees from Duke University and completed training in internal medicine at the Johns Hopkins Hospital, where he served as chief medical resident. He was a clinical fellow in medical oncology at the Dana-Farber Cancer Institute and later a postdoctoral fellow in David Livingston’s laboratory, during which time he was a McDonnell Scholar.
Among his many distinguished awards, Dr. Kaelin is the 2019 Nobel Prize recipient in Physiology or Medicine for his discoveries of how cells sense and adapt to oxygen availability. These findings have paved the way for promising new strategies to fight a wide range of disorders, including cancer, cardiovascular disease, anemia and many others.
Other notable honors include the 2018 Massry Prize given by the Meira and Shaul G. Massry Foundation to recognize his outstanding contributions to the biomedical sciences and the advancement of health; the 2016 Lasker Award for medical science; the Grand Prix of the Fondation Lefoulon-Delalande from the Institute of France in 2012 and the 2010 Canada Gairdner International Award for his contributions to the field of cardiovascular research. He also received the Helis Award in 2018, and the Science of Oncology Award from the American Society of Clinical Oncology and the Princess Takamatsu Award from the American Association for Cancer Research, both in 2016.
Dr. Kaelin is a member of the National Academy of Sciences, the National Academy of Medicine, the American Society of Clinical Investigation and the American College of Physicians and a Fellow of the AACR Academy. He recently served on the NCI Board of Scientific Advisors, the AACR Board of Trustees, and the Institute of Medicine National Cancer Policy Board.
2006
The Hale Family Award
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