Abstract
Abstract There have been great advances in receptor-targeted breast cancer therapeutics. However, limited sensitivity and tumor resistance remain significant problems for many patients. To overcome these obstacles our laboratory has focused on targeting HSP90, a global mediator of oncogenic pathways involved in nearly all cancer types. Our laboratory has developed PU-H71 which selectively inhibits oncogenic HSP90 and is one of the first targeted therapies to show preclinical potent activity in the treatment of triple negative breast cancers. Here, we investigate how the complex biology of different types of breast tumors influences response to HSP90 inhibition. Our preliminary data indicate that sensitivity to PU-H71 goes beyond a tumor's receptor status and is highly driven by its intracellular protein composition. Our objective is to identify specific pharmacodynamic changes in select HSP90 onco-client proteins and regulators of apoptosis associated with HSP90 inhibition as a tool to monitor therapeutic response. Using several different breast cancer cell lines we evaluate how alterations in specific onco-client phosphorylated species as well as the induction of pro-apoptotic protein cleavage correlates to a tumor's sensitivity to HSP90 inhibition. In addition to testing cell lines, we have developed a system to investigate PU-H71 on primary tumors by treating surgery specimens ‘ex vivo’ (fresh tissue sectioning) to determine response and pharmacodynamic alterations in patient samples. Our long term goal is to establish specific pharmacodynamic changes (PD markers) that correlate to tumor sensitivity allowing us to better predict those patients more likely to benefit from HSP90 inhibition i.e. PU-H71 therapy. Citation Format: Matthew Riolo, Shanu Modi, Adriana Corben, Clifford Hudis, Mary Alpaugh, Gabriela Chiosis. A comprehensive study to analyze tumor sensitivity to HSP90 inhibition therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5598. doi:10.1158/1538-7445.AM2013-5598
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