Therapeutic targeting of HSP90-dependent signaling

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DESCRIPTION (provided by applicant): Despite the recent identification of additional drugs with activity in ovarian cancer, including gemcitabine, topotecan and liposomal doxorubicin, the vast majority of patients with stage Ill/IV ovarian cancer succumb to this disease. This observation highlights the need for improved methods to circumvent drug resistance in ovarian cancer. Emerging evidence suggests that many of the same changes that contribute to the development of ovarian cancer might also contribute to drug resistance. Signaling from the cell surface receptors HER2/neu and insulin-like growth factor receptor (IGFR) activates the phosphatidylinositol-3 (PI3) kinase/Akt pathway, which inhibits apoptosis, and the Ras/Raf/MEK/Erk pathway, which enhances proliferation. In addition, checkpoint kinase signaling that is activated by replication stress and DNA damage plays a critical role in determining whether cells will restore homeostasis or undergo apoptosis. Interestingly, the ongoing activity of the heat shock protein 90 (HSP90) chaperone complex is critical for the stability and function of components of all of these pathways. The central hypothesis underlying this project is that HSP90 directed therapy would overcome chemotherapy resistance in ovarian cancer through inhibition of proliferation and survival signaling. Our preliminary studies demonstrate that 17-allylamino-17- demethoxygeldanamycin (17-AAG) or geldanamycin (GA) causes downregulation of HER2, IGFR, and Akt in multiple ovarian cancer cells. Additional experiments demonstrate that 17-AAG inhibits the activation of checkpoint kinase 1 (Chk1) and enhances the cytotoxicity of gemcitabine in OVCAR-3 cells. Finally, our ongoing phase I study has demonstrated that 17-AAG successfully targets the HSP90 complex in patients at therapeutically achievable doses and that 17-AAG can be combined with cisplatin and gemcitabine in the clinical setting. We now propose to 1) to determine how HSP90 participates in gemcitabine-triggered Chk1 signaling in ovarian cancer cells; 2) assess the extent to which 17-AAG sensitizes various ovarian cancer cells to gemcitabine, cisplatin, and topotecan and determine whether differences in sensitization reflect variations in HSP90 chaperone complex function and/or levels of HSP90 clients; and 3) to evaluate the clinical and biologic effects of 17-AAG alone and when combined with gemcitabine or cisplatin in ovarian cancer patients. Collectively, these studies will provide information about the ability to alter the response of ovarian cancer cells to chemotherapeutic agents in vitro and in the clinical setting.