This lecture is the 24th in the series of Royal Academy Nobel Laureate Lectures hosted by Royal Academy together with Novo Nordisk Foundation. 

Watch the lecture here:

Professor William Kaelin writes the following about the lecture:

Loss of the VHL tumor suppressor protein (pVHL) is the usual initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer.   A pVHL-containing ubiquitin ligase targets the alpha subunits of the HIF transcription factor for proteasomal degradation. Binding of pVHL to HIFα requires that HIFα be prolyl hydroxylated by the EglN 2-oxoglutarate (2-OG)-dependent dioxygenases, which act as oxygen sensors. HIF2α promotes ccRCC and HIF1α inhibits ccRCC in preclinical models. Drugs that inhibit the HIF-responsive gene product VEGF are mainstays of kidney cancer treatment.  The allosteric HIF2α inhibitor Belzutifan was recently approved for the treatment of VHL Disease (caused by germline VHL mutations) and has advanced to Phase 3 testing in sporadic ccRCC based on promising Phase 2 data. ccRCC is also known to be immunogenic despite having a low mutational burden relative to other immunogenic cancers. Earlier work by others suggested that this might be due, at least partly, to increased endogenous retrovirus expression (ERV). We found that multiple ERVs are regulated by HIF2, including some that can give rise to HLA-bound peptides. 

EglN inhibitors are being developed as treatments for anemia and ischemia.  Curiously, ischemia of a given tissue/organ can protect other tissues/organs at s distance against subsequent ischemic insults. Our recent work suggests that this is due to increased circulating 2-OG and kynurenic acid (KynA). KynA activates the orphan GPCR GPR35 and thereby conserves ATP during ischemia.  We have also discovered a mechanism that explains the tissue protective effects of SGLT2 inhibitors.

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, and the American College of Physicians. 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.

Portrait: Sam Ogden