|Albert Baldwin Jr., Ph.D.||Mark Lemmon, Ph.D.||Kevan Shokat, Ph.D.|| William Weiss, M.D., Ph.D.
|University of North Carolina, Chapel Hill||University of Pennsylvania
||University of California, San Francisco||University of California, San Francisco|
HER Family Kinases and Oncogene Addiction
The war on cancer has illuminated a basic wiring diagram through which normal cells respond to nutrients, linking the abundance of such nutrients to regulated increases in cell growth. We now also understand some ways in which this wiring is altered in cancer cells, which can grow in a deregulated manner even in nutrient poor conditions. As a result of this understanding, a number of drugs (targeted agents) have been developed against potential key switches or nodes in this wiring. Only a few of these targeted agents have led to improved survival for patients.
In lung cancer in particular, therapies targeting Epidermal Growth Factor Receptor (EGFR), the founding member of four HER proteins (Human EGFR-family) represent a robust therapy. While a targeted agent that blocks HER1 in lung cancer leads to improved outcome for patients, the identical agent is ineffective in brain cancers, even though inappropriate activation of HER1is common to both cancers. It is also intriguing that the failure of HER1-directed therapy in many forms of cancer is due to inappropriate activation of a second family member, HER3. It appears that targeting HER1in some cancer cells leads to activation of HER3 as an evasive maneuver.
The successes and failures of HER1 directed therapies in patients, and the intriguing role played by HER3 in contributing to these failures, form the basis for our application. These four scientists at three institutions on two coasts. They propose to leverage our complementary expertise to clarify: 1) The biology of HER family signaling in cancers, focusing on brain cancer, 2) How different HER family members interact with one another in cells, and 3) How different combinations of HER family members act to rewire cancer cells, thereby evading therapies directed against specific HER targets.
Dr. Lemmon is a basic scientist and an expert on the basic biology and function of HER proteins. Dr. Shokat is a basic scientist and an expert on chemical approaches to develop drugs and drug-like molecules that kinases, including HER kinases. Dr. Baldwin is a basic scientist with specific expertise on how HER proteins, which live on the surface of cells, relay information within the cell, leading to deregulated growth. Dr. Weiss is a physician scientist with expertise in testing new therapies in model systems to facilitate translating such approaches to patients.
Through regular interactions and collaborations, their group aims to better understand interactions among this complex family of proteins, and how to most efficiently target these proteins in cancers in which HER proteins play a prominent role.
*Albert Baldwin Jr., is also collaborating with Alan Friedman on another grant project. Click here to read more.