Understanding how selective inhibition of cyclin-dependent kinases (Cdks) affects normal and tumor cell growth may lead to novel treatment strategies for cancer. Cdks are a conserved family of serine/threonine kinases that serve a central role in regulating the eukaryotic cell cycle. Cdk2 and Cdk1 are generally thought to control the S and M phases of the vertebrate cell cycle, respectively. Their exact function in vertebrate cells has been difficult to define because there are no truly specific inhibitors that distinguish between Cdk1 and Cdk2. The essential role of Cdks in cell cycle progression makes them a target of great interest for the development of specific inhibitors as anti-cancer agents. Tumor cells develop a deregulated cell cycle that may render their growth especially sensitive to Cdk inhibition. This raises the possibility that Cdk inhibition may result in the predominant killing of tumor cells while sparing normal cells. Currently no murine model exists to validate the role of specific Cdk inhibition in developing tumors. The long-term goal of the candidate, and this proposal, is to understand how normal and tumor cells respond to Cdk inhibition and to apply this knowledge to develop new therapeutic strategies against cancer. First, we will examine the effect of Cdk inhibition in the context of cells transformed by a variety of oncogenes. Transgenic mouse tumor model systems will be bred to strains harboring oncogenes that render cells sensitive to Cdk inhibition. We will test if Cdk inhibition can mediate significant regression of endogenous tumor, or prevent de novo tumor development. Second, mutant forms of Cdks that can be selectively inhibited in vivo by soluble small molecules will be generated. Third, we will determine the precise cell cycle arrest points and cellular consequences associated with Cdk1 and Cdk2 inhibition. The candidate is a physician-scientist currently pursuing post-doctoral training who is proposing a 5-year mentored research experience with J. Michael Bishop and David Morgan at the University of California, San Francisco. The proposed training program is designed with the goal of preparing this applicant to establish an independent laboratory in an academic oncology department. ? ?
