Biography
William G. Kaelin Jr., M.D., is a Professor in the Department of Medicine at the Dana-Farber Cancer Institute and at the Brigham and Women's Hospital, Harvard Medical School. 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 the laboratory of David Livingston, during which time he was a McDonnell Scholar.
Dr. Kaelin is a member of the American Society of Clinical Investigation and the American College of Physicians. He recently 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 and the Richard and Hinda Rosenthal Prize from the AACR.
A Howard Hughes Medical Investigator since 1998, 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 led to new insights into how cells sense and respond to changes in oxygen, and thus has implications for diseases beyond cancer, such as myocardial infarction and stroke.
Abstract
Translational Studies Based on Tumor Suppressor Proteins
Over 30,000 Americans are diagnosed with kidney cancer each year resulting in approximately 12,000 kidney cancer-related deaths per year. About 1 in 35,000 people are born with a defective copy of the VHL gene and are at increased risk of kidney cancer. Importantly, acquired (rather than inherited) mutations of the VHL gene are also very common in non-hereditary kidney cancer. In short, inactivation of the VHL gene is a common event in both hereditary and non-hereditary kidney cancer. Genes are usually ‘blueprints’ for making particular proteins. The VHL gene contains the information for making the VHL protein (‘pVHL’), which inhibits a protein called ‘HIF’. HIF, in turn, activates ~ 100 genes implicated in cell growth and angiogenesis (the process of making new blood vessels), including VEGF. Most successful drugs work by binding to, and inhibiting, a specific cellular protein (its ‘target’). Drugs that inhibit VEGF have demonstrated significant activity as treatments for kidney cancer, in terms of tumor shrinkage and delayed tumor growth, but are not curative. This proposal seeks to build upon these results. One set of experiments seeks to identify new kidney cancer drug targets by systematically searching for genes that are essential for survival in cells lacking pVHL, but not in normal cells. In theory, drugs that inhibited the proteins encoded by such genes should selectively kill tumor cells bearing VHL mutations. Inactivation of the VHL gene is not sufficient to cause kidney cancer; mutations of additional genes are also clearly required.
State of the art techniques will be used to try to identify such genes because they should define additional molecular circuits that are abnormal in kidney cancer cells. These circuits could then be targeted with drugs. This proposal will also attempt to identify proteins (‘biomarkers’) that can be easily measured in clinical samples (such as blood or urine) to monitor the presence of kidney cancers in patients and/or to document that kidney cancer drugs have successfully inhibited their targets. In some cases drugs will already be available, or in development, for the targets identified in this proposal. In other cases partnerships with the private sector will be required to develop such drugs. The final goal of this proposal is to perform kidney cancer clinical trials with novel drugs that are based on knowledge of the genes that are altered in this disease, as outlined above.