The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Willliam Kaelin, M.D., Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute; Harvard Medical School; investigator, Howard Hughes Medical Institute

Speaker bio(s)

Inactivation of the VHL tumor suppressor gene is the usual initiating event in hereditary (VHL Disease) and sporadic clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. Other tumors linked to VHL inactivation include hemangioblastomas and paragangliomas. The VHL gene product, pVHL, is part of a ubiquitin ligase that targets the alpha subunits of the HIF transcription factor for degradation. Binding of pVHL to HIFα requires that HIFα be modified by oxygen-sensitive prolyl hydroxylases.

Of the HIF paralogs, HIF2α promotes ccRCC and HIF1α inhibits ccRCC in preclinical models. Drugs that inhibit the HIF-responsive gene product VEGF are mainstays of ccRCC treatment. A first-in-class allosteric HIF2α inhibitor has also been recently approved for sporadic ccRCC and for VHL Disease.

ccRCCs are immunogenic, despite having a relatively low burden of missense mutations. The Kaelin Lab discovered that HIF regulates many relatively intact endogenous retroviruses that can be transcribed, translated, and presented as immunogenic HLA-bound peptides.

William Kaelin's group and Ben Ebert’s group showed that the thalidomide-like drugs reprogram the cereblon ubiquitin ligase to target two myeloma oncogenic transcription factors, IKZF1 and IKFZ3, for destruction. They recently developed a positive selection, mechanism agonistic, assay for protein degraders and used it to identify chemicals that inactivate mutant beta catenin.

William Kaelin is the Sidney Farber Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute, Senior Physician-Scientist at Brigham and Women's Hospital and Howard Hughes Medical Institute Investigator. He obtained his undergraduate and M.D. degrees from Duke University and completed his 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.

A Nobel Laureate, Dr. Kaelin received the 2019 Nobel Prize in Physiology or Medicine. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the National Academy of Medicine, the American Society of Clinical Investigation, the American College of Physicians and the American Philosophical Society. He previously served on the National Cancer Institute Board of Scientific Advisors, the AACR Board of Trustees, and the Institute of Medicine National Cancer Policy Board. He is a recipient of the Paul Marks Prize for cancer research from the Memorial Sloan-Kettering Cancer Center; the Richard and Hinda Rosenthal Prize from the AACR; the Doris Duke Distinguished Clinical Scientist award; the 2010 Canada International Gairdner Award; ASCI’s Stanley J. Korsmeyer Award; the Scientific Grand Prix of the Foundation Lefoulon-Delalande; the Wiley Prize in Biomedical Sciences; the Steven C. Beering Award; the AACR Princess Takamatsu Award; the ASCO Science of Oncology Award; the Helis Award; the Albert Lasker Basic Medical Research Prize; the Massry Prize; the Harriet P. Dustan Award for Science as Related to Medicine from the American College of Physicians.

Dr. Kaelin’s research seeks to understand how, mechanistically, mutations affecting tumor-suppressor genes cause cancer. His laboratory is currently focused on studies of the VHL, RB-1, and p53 tumor suppressor genes. His long-term goal is to lay the foundation for new anticancer therapies based on the biochemical functions of such proteins. His work on the VHL protein helped to motivate the eventual successful clinical testing of VEGF inhibitors for the treatment of kidney cancer. Moreover, this line of investigation led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as anemia, myocardial infarction, and stroke. His group also showed that leukemic transformation by mutant IDH was reversible, setting the stage for the development and approval of mutant IDH inhibitors, and discovered how thalidomide-like drugs kill myeloma cells by degrading two otherwise undruggable transcription factors

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Tri-Institutional