? DESCRIPTION (provided by applicant): Prostate cancer (PCa) mortality is caused by the formation of metastases. This is a major problem for US veterans. Processes that drive the development of metastases, such as increased cell motility, therefore represent high value therapeutic targets. All attempts to selectively therapeutically target cell motility and consequent metastasis have failed. We approached this intractable and important problem by designing a unique strategy that used small chemicals as highly refined probes to identify novel and important biological regulatory sites. This led us to synthesize the probe, KBU2046, which inhibits phosphorylation of Ser226 on HSP90?. Phosphorylation of Ser226 drives cell invasion and mediates KBU2046 anti-invasion efficacy. When administered orally, KBU2046 inhibits human PCa metastasis in mice at nM concentrations. Knowing that HSP90 chaperone action maintains androgen receptor (AR) in its functional state, we went on to demonstrate that KBU2046-mediated disruption of HSP90 function inhibits AR signaling and AR-driven cell growth. Finally, comprehensive preclinical toxicity and pharmacology studies all support that KBU2046, as a drug, will have a high potential for activity in humans. We hypothesize that our chemical probe strategy has identified modulation of HSP90? Ser226 phosphorylation as a novel and selective mechanism regulating metastatic progression, that KBU2046 efficacy is due, at least in part, to modulation of client protein binding to HSP90?, resulting in changes in Ser226 phosphorylation status, and that this strategy provides a viable pathway for inhibiting PCa metastasis in humans. Aim 1. Characterize the molecular mechanism by which KBU2046 affects client protein binding and Ser226 phosphorylation. KBU2046 does not directly inhibit kinase function. It alters binding of client proteins to HSP90?, and appears to do so through stabilization of the HSP90?/CDC37 heterocomplex. Studies will fully characterize KBU2046 induced changes in client protein binding to HSP90?, and will go on to assess how they affect Ser226 phosphorylation status and cell motility. Aim 2. Evaluate KBU2046 efficacy in clinically relevant human PCa murine xenograft models. Aim 2A examines whether KBU2046 enhances the efficacy of hormone therapy, and delays emergence of resistance to it. Experiments in Aim 2B build upon our recent finding that KBU2046 selectively suppresses osteonectin expression. Osteonectin is an extracellular matrix protein, which has been shown to drive metastasis in human PCa. We hypothesize that KBU2046 will disrupt PCa cell dissemination to bone, and will test this using an intra-cardiac injection model of metastasis. Impact. Studies will increase our understanding of the basic biology of cancer cell motility and metastasis, and will inform us of the optimal means to modulate it in humans.
|Effective start/end date||1/1/16 → 12/31/19|
- National Institutes of Health
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