A leader among researchers seeking to understand how, mechanistically, mutations affecting tumor-suppressor genes cause cancer, Dr. Kaelin studies the functions of proteins encoded by specific tumor-suppressor genes; his findings have had major clinical implications for several forms of cancer, particularly renal cell carcinoma (RCC). He demonstrated that inherited mutations of the tumor-suppressor gene, von Hippel–Lindau (VHL), cause aberrant blood vessel formation that is characteristic of VHL disease, a rare hereditary disease. Spontaneously arising VHL mutations were also shown to be extremely common in both hereditary and sporadic RCC. Dr. Kaelin has since demonstrated that by restoring VHL function, RCC growth may be suppressed.
Dr. Kaelin’s work involving the VHL protein (pVHL) led him to investigate its role in the regulation of hypoxia-inducible factor (HIF), which controls genes that are activated under low oxygen conditions. These studies proved that pVHL binds to HIF when oxygen is present and targets it for destruction. When pVHL is mutated, the protein is unable to bind to HIF, resulting in inappropriate HIF accumulation and the transcription of genes that promote blood vessel formation, such as vascular endothelial growth factor (VEGF). This finding has proved important in the understanding of the pathogenesis of RCC, as VEGF is directly linked to the onset of RCC through its ability to promote angiogenesis.
These fundamental studies led by Dr. Kaelin have resulted in FDA approval of five VEGF inhibitors for the treatment of metastatic RCC as well as two mTOR inhibitors, which he and others showed also indirectly block VEGF. New areas of research in RCC involving VEGF include developing more potent and better-tolerated agents and defining the role of combination and sequential anti-VEGF regimens. Dr. Kaelin’s investigations into how cells sense and respond to changes in oxygen have also led to promising new treatments for anemia, myocardial infarctions, and stroke.
2019 Nobel Prize in Physiology or Medicine
2014 Wiley Prize in Biomedical Sciences
2012 Stanley J. Korsmeyer Award, American Society for Clinical Investigation
2012 Foundation Lefoulon, Delalande Grand Prix for Science, Institut de France
2011 Alfred G. Knudson Award for Excellence in Cancer Genetics, National Cancer Institute
2010 Elected Member, National Academy of Sciences, Washington, DC
2010 Canada Gairdner International Award
2007 Elected Member, Institute of Medicine
2007 Duke University School of Medicine Distinguished Alumnus Award
2006 AACR-Richard and Hinda Rosenthal Award
2006 Doris Duke Distinguished Clinical Scientist Award
2003 Elected Member, Johns Hopkins Society of Scholars
2001 Paul Marks Prize for Cancer Research, Memorial Sloan-Kettering Cancer Center
1993 Scholar Award, James S. McDonnell Foundation
1982 MD, Duke University School of Medicine, Durham, NC