William G. Kaelin, Jr., MD, of Dana-Farber Cancer Institute, was presented with the 2012 American Society for Clinical Investigation's Stanley J. Korsmeyer Award, in recognition of his contributions to the molecular understanding of cellular oxygen sensing and cellular adaptation to hypoxia. Kaelin was selected as a co-recipient with Gregg L. Semenza, MD, PhD, of Johns Hopkins University School of Medicine.
Kaelin and Semenza's work has defined how this sensing mechanism goes awry in broad spectrum of disorders ranging from the vascular overgrowth associated with many forms of cancer to the reduced vascular density associated with ischemic disease. The Korsmeyer Award also recognizes their success in mentoring future physician-scientists and researchers.
As part of the honor, Kaelin and Semenza shared the $10,000 honorarium and presented the Korsmeyer Lecture at the 2012 American Society for Clinical Investigation/Association of American Physicians Joint Meeting in Chicago on April 29.
Kaelin was recognized for his work that provided a molecular explanation for the hypervascularity of the kidney and brain tumors seen in patients with germline mutations in the von Hippel Lindau (VHL) gene. He showed that VHL-deficient tumor cells produce high levels of hypoxia-inducible gene products, including VEGF, irrespective of oxygen levels.
This work led to a series of key discoveries into how cells sense and respond to changes in oxygen levels. One of the most significant discoveries was that the VHL protein interacts with HIF in an oxygen-sensitive manner and suppresses tumor formation by targeting HIF for degradation.
When a defective VHL-HIF interaction exists due to mutations in VHL, there are increased HIF levels that promote vascular tumor formation. Kaelin’s laboratory also discovered that oxygen-dependent proline hydroxylation of HIFs by a prolyl hydroxylase (PHD2) regulates its ubiquitination by VHL and subsequent degradation. The functional link between these components of the oxygen-sensing network is reflected by the fact that mutations in the genes encoding all three components (PHD2, VHL, or HIF) lead to hereditary polycythemia.
The insights gained from defining the VHL-HIF interaction created a conceptual basis for the successful clinical testing of VEGF inhibitors for metastatic kidney cancer.
Kaelin was elected to the ASCI in 1997 and has received numerous honors for his research, including the Canada Gairdner Award, and is a member of the National Academy of Sciences and the Institute of Medicine.
Kaelin obtained his undergraduate and medical degrees from Duke University. He completed training in Internal Medicine at Johns Hopkins Hospital and was a clinical fellow in Medical Oncology at Dana-Farber. Kaelin is currently professor in the Department of Medicine at Dana-Farber and at Brigham and Women’s Hospital, Harvard Medical School and is a Howard Hughes Medical Institute Investigator.