The central hypothesis of the proposed research is that critical determinants of clinical sensitivity to anticancer drugs can be identified and modulated in patients. It is estimated that approximately 90 percent of cancer deaths are related to resistance to chemotherapy. Development of improved, novel treatments is therefore critical to the current and future practice of oncology. The proposed research program has the potential to identify clinically significant resistance mechanisms and promote rapid translation of novel treatments into early-phase clinical trials. The goal of these trials will be to establish feasibility of modulation-"proof-of-principle"-in human subjects, using biochemical and/or molecular intermediate endpoints. Mentoring of next-generation clinical investigators in the conduct of translational therapeutic investigations is also proposed, as progress against drug resistance will likely require the concerted efforts of current and future investigators. The proposed research includes three specific aims: (1) To quantitate relationships between expression of genes encoding survival factors and post-chemotherapy outcomes of patients with advanced ovarian carcinoma; (2) To perform initial clinical trials of novel treatment strategies designed to circumvent resistance to chemotherapy; and (3) To mentor beginning clinical investigators in the design and conduct of translational therapeutic trials. This Midcareer Investigator Award supports these patient-oriented research and mentoring activities of the candidate while promoting his immediate and long-term career development. The candidate's immediate career objectives are: (1) to continue current clinical correlative projects in ovarian carcinoma and melanoma, (2) to conduct mechanistic early-phase trials, (3) and to promote a clinical culture that values and supports such activities. His long-term career objectives are: (1) to develop and sustain an outstanding program in translational therapeutics and (2) within this program, to develop improved treatment strategies based on modulation of critical mechanisms that determine sensitivity to chemotherapy.