William G. Kaelin, Jr., MD

2007-2008 BCRF Project:
Last year, with BCRF support, Dr. Kaelin and his team succeeded in making tools to 'silence' the EglN2 gene in human breast cancers. Using these tools, they showed that inactivation of EglN2 significantly diminishes the ability of human breast cancers to proliferate when grown in plastic dishes or in laboratory models that recapitulate aspects of tumor growth in women.

They will continue their studies for one more year to determine if the incidence of breast cancer is decreased in models where EglN2 is inactivated. If breast cancer growth is shown to be slowed this will serve to "validate" EglN2 as a drug target in breast cancer and would predictably motivate efforts by the pharmaceutical industry to develop drugs that inhibit EglN2 for the treatment of breast cancer, especially since there is currently a shortage of well-validated breast cancer targets. EglN2 inhibitors might, if this hypothesis is correct, be especially useful for the more than 50% of breast cancers that over-produce Cyclin D1, including tumors that have acquired resistance to anti-estrogens such as Tamoxifen.

Mid-Year Progress Report:
Dr. Kaelin reports that his group has bred models that lack a protein called EglN2 with models that develop breast cancer because they were engineered to overproduce the Her2/Neu protein in their mammary glands. So far it appears that those lacking EglN2 are partially protected against breast cancer. Since EglN2 is dispensable in these models and can be inhibited with "drug-like" chemicals, the researchers are now using genetic and pharmacological tools to inhibit EglN2 in a panel of human breast cancers to gain a fuller understanding of whether EglN2 inhibitors are likely to be useful breast cancer drugs.

Bio:
Dr. Kaelin 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 MD 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.