The proposed research addresses two high priority areas identified by the Prostate Cancer Progress Review Group: the role of novel therapeutic agents directed at new targets and the use of relevant biomarkers to monitor clinical response. The studies proposed will be performed in the context of phase I a clinical trial of 17-N-allylamino-17-demethoxy geldanamycin (17-AAG), the first ansamycin antibiotic to enter clinical testing. Ansamycin antibiotics are a new class of compounds that induce the selective degradation of proteins which bind to the Hsp 90 family of chaperones. Hsp90 is required for protein refolding after stress, and for the conformational maturation of nuclear steroid receptors, certain protein kinases and other regulators of cell cycle control. Preclinical work by us and others has shown that malignant cells that express the androgen receptor (AR), the estrogen receptor (ER), HER2 and which overexpress cyclin D1 are sensitive to these agents, making prostate, breast and colon cancers of particular therapeutic interest. Approval to conduct a phase I clinical trial using of 17-AAG using an accelerated titration design has been obtained (LOI-98-355, Approval Date 4/15/99) and approved by the MSKCC Institutional Review Board (Protocol No. 99-37, Approved 5/25/99). In addition to the safety assessments and pharmacokinetic studies that are a routine part of the phase I study, we propose to conduct clinical and laboratory investigations to understand which tumors may be most sensitive, and which target proteins are affected in vivo. We will focus on the expression of the AR (prostate), ER (breast), HER2 and cyclin D1 in tumor biopsies obtained prior to and following treatment, proteins we have shown to be decreased by and which mark for sensitivity to the compound in vitro. These same proteins will be evaluated in circulating tumor cells isolated from the peripheral blood. To assess response, we will explore serial changes in FDG uptake using positron emission tomography. In vitro studies of established cell lines will also be conducted to explore the timing of the effects on specific proteins, and for other markers of drug effect. Preliminary data suggest that the accumulation of lipid droplets (prostate cancers) or fat (breast cancer) may mark for a differentiation effect of the drug.
