Pharmacology Shared Resource

The Developmental Therapeutics Program, an established program of the Cancer Center, contributes to more effective treatment of malignant disease through e spectrum of basic end translational research. The AIMS ere to 1) define cellular pathways involved in survival end proliferation in order to improve understanding of response to established treatments end identify new therapeutic targets; 2) elucidate the mechanisms of action of novel anticancer agents end identify biochemical changes resulting in resistance to these agents; 3) evaluate potential genetic contributions to efficacy and toxicity of anticancer treatments; end 4) assess the toxicity end initial activity of selected treatments in early phase clinical trials, with an emphasis on correlative studies that assess pharmacokinetics, pharmacogenetics end biological effects of agents in tumor cells. Forty-five members from 17 departments end divisions contribute to this effort, with total funding of $23.3M ($11.9M peer-reviewed, with 60.3% from NCI and 89.3% from the NIH overall). Since the lest competitive renewal, the program has generated 724 publications, 19% end 57% reflecting intra- end inter-programmatic collaborations, respectively. Notable accomplishments include demonstration that 1) the temoxifen metabolite endoxifen, which bypasses an important metabolic block in some patients, has activity in preclinical studies end early phase clinical trials; 2) PARP inhibitors kill BRCA1/2-mutent cells through e process that involves activation of the nonhomologous end-joining pathway, yielding e unique responder/no responder hypothesis that is being tested clinically; end 3) FKBP51, MMSET end cereblon ere important determinants of response to various therapies. Leadership of the program is provided by Scott Keufmenn, MD, PhD, end Zhenkun Lou, PhD. The program makes extensive use of Shared Resources, especially the cell analysis, proteomics, pathology research, gene analysis, pharmacology end pharmacy facilities, as well as the Clinical Research Office. Future goals of the program include the establishment of e focus on oncogene-induced metabolic changes as therapeutic targets in cancer, growth of a nascent screening/drug discovery effort, end encouragement of additional genomically guided trials to follow recently opened studies.