Heat shock protein 90 as modulator of tumor cell survival

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Description (provided by applicant) The signal transduction pathways which control tumor Cell survival provide an attractive, rational target for the development of new anticancer agents. A particularly effective approach to inhibiting these pathways could be provided by drugs which alter the function of heat shock protein 90 (Hsp 90). This ubiquitously expressed molecular chaperone is not mutated in cancer. Instead, it appears to play an essential role in promoting minor cell survival by enhancing the stability and activity of multiple growth factor receptors, kinases and transcription factors. Although an attractive target conceptually, Hsp 90 function has never before been exploited therapeutically. As a result, the best manner in which to administer and evaluate novel Hsp 90-binding drugs such as 17-Nallylamino-17-demethoxygeldanamycin (hAAG) and chlorobiocin remains largely unknown. To address these issues, this project seeks to validate Hsp 90 as a useful chemotherapeutic target by defining practical, predictive molecular endpoints for assessment of drug action in cancer patients. The hypothesis to be tested is that the anticancer activity of Hsp 90-binding drugs results, at least in part, from the alterations in tumor cell survival signaling pathways which they induce. To test this hypothesis, the following experimental plan is proposed: 1. To develop new molecular assays based on innovative technologies such as laser scanning cytometry and real time PCR to measure drug-induced alterations in the very limited amounts of tumor and normal tissue which can realistically be obtained from patients. 2. To apply the assays developed in vitro to quantitate drug-induced alterations of specific molecular endpoints in normal and tumor tissues harvested from mice. 3. To correlate anti-tumor responses in cancer patients receiving Hsp 90- binding drugs with alterations in molecular endpoints and the results of non-invasive imaging procedures. Overall, the goal is to generate an understanding of how best to administer and measure the effects of both Hsp 90-binding drugs and molecularly targeted therapeutics in general. The insights gained are expected to contribute to significant improvements in the prevention and cure of cancer.