Targeting myristoylation of Src family kinases for inhibition of prostate tumorig

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DESCRIPTION (provided by applicant): The expression and activity of Src family kinases (SFKs) are highly elevated in numerous human cancers, including prostate cancer. SFKs are pleiotrophic activators in several signal transduction pathways. Targeting SFKs has a favorable inhibitory effect on proliferation of tumorigenic cells and bone metastasis in advanced castration-resistant prostate cancer patients. The SH4 domain of SFKs contains conserved sites for myristoylation, and palmitoylation modification depending on SFK members, which regulate SFKs trafficking intracellularly. The localization of SFKs at the cytoplasmic microdomain is critical to mediating cell signaling, exhibiting their activity, and illuminating their tumorigenic potential in cancer cells. Preliminary data suggest that myristoylated, but not palmitoylated, SFKs facilitate prostate tumorigenesis. In this proposal, investigators at the Medical University of South Carolina hypothesize that targeting myristoylation of SFKs inhibits their tumorigenic potential in prostate cancer. They will investigate if loss of myristoylation will attenuate SFK-induced tumorigenesis, inhibit Src kinase to interact with down- stream substrates such as androgen receptor, and suppress SFK-mediated paracrine signaling and over- expression of FGF10-induced tumorigenesis. The investigators will utilize myristoylation-defective SFK mutants and in complement a small molecule N-myristoyltransferase inhibitor, COPP-24, in a prostate regeneration assay to define the role of myristoylation in prostate tumorigenesis in vivo. This study will demonstrate that myristoylation of SFKs is a target for inhibiting prostate tumorigenesis and will evaluate the efficacy of a novel anti-neoplastic agent that blocks myristoylation of SFKs in treating prostate cancer.