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.

Public Health Relevance

The expression and activity of Src family kinases (SFKs) are highly elevated in numerous human cancers, including prostate cancer. This proposal will demonstrate that myristoylation of SFKs is a target for inhibiting prostate tumorigenesis, and evaluate the efficacy of a novel anti-neoplastic agent that blocks myristoylation of SFKs in treating prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA172495-01
Application #
8420668
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (09))
Program Officer
Arya, Suresh
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$309,175
Indirect Cost
$101,675
Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602