The lethality of prostate cancer (PCa) is attributable to the metastatic castration resistant state (CRPC). Accordingly, an understanding of the biochemical and genetic alterations that drive metastasis and castration resistance offers the potential and promise of identifying molecular targets for therapeutic intervention. During the current SPORE funding period, we have made significant advances in the elucidation of key signaling pathways that mediate castration resistance and metastasis. To investigate the molecular underpinnings of metastasis in Aim 1 of our proposal, we will use our recently developed mouse model in which the PI3K/AKT and Ras/MAPK pathways are simultaneously altered, as seen in humans, in a prostate-specific fashion. The double mutants spontaneously develop metastases, which are absent in mice with single pathway alterations. Thus, these mouse models will allow us to establish the role of interactions between the PI3K/AKT and Ras/MAPK pathways in the development of metastasis as well as castration resistance and screen for therapeutic agents that can prevent or delay metastatic progression. Our recent studies also identified a novel mechanism of PI3K/AKT activation in response to androgen deprivation therapy, which leads to castration resistant growth. Conversely, PISK inhibition results in enhanced AR transcriptional output. Thus, the compensatory activation of one of these pathways in response to inhibition of the other represents a

Public Health Relevance

: PCa mortality is invariably associated with the development of metastases and resistance to castration. We have designed experiments in mice and a clinical trial in patients to elucidate the crucial biochemical signals that promote the metastatic and castration resistant states. We will not only gain a better understanding of these lethal processes, but more importantly, identify relevant drug targets and specific drugs that can be applied to patients who suffer from deadly forms of PCa.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
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Special Emphasis Panel (ZCA1-RPRB-M (M1))
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University of California Los Angeles
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