This proposal ? tyrosine kinases and prostate cancer? began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in neuroendocrine differentiation and androgen independence were identified and the processes characterized. This led to the discovery of a complex of tyrosine kinases Src, Etk and FAK (referred to as Src kinase complex) as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. These tyrosine kinases present novel targets for potential therapeutic intervention. The present proposal is focused on prostate cancer biology and etiology, especially the involvement of Src/Etk tyrosine kinase complex in prostate carcinogenesis and androgen independence conversion. The potential of Src and Etk to serve as therapeutic targets will be explored. Our results in the past grant period contributed to the basic understanding of the roles of neuroendocrine differentiation and neuropeptide in androgen independent growth of prostate cancers, the involvement of Src kinase complex in inappropriate activation of androgen receptor, and the oncogenic role of Etk tyrosine kinase in prostate carcinogenesis. In addition, with our collaborators, we developed in vivo prostate cancer mouse models and potential inhibitors for the Src/Etk complex. Yet, the detailed mechanisms whereby Src kinase complex activates androgen receptor and the inhibitors of Src kinase complex induce cell killing remain largely unknown. Taking advantage of the discoveries and the reagents developed in the past grant period, the present proposal is designed to provide a better understanding of the mechanisms whereby Src tyrosine kinase complex activates androgen receptor and protects prostate cancer cells from autophagic and apoptotic death. Project Narrative One of the most troubling aspects of prostate cancer is its evolution to androgen independence, to which no effective treatment has been developed. The present proposal deals directly with the mechanisms of this evolution and has identified several key tyrosine kinases involved in this process. In addition, this proposal will provide important information concerning the mechanisms of cell killing by tyrosine kinase inhibitors and test the potential benefits of using these inhibitors in treating prostate cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK052659-10S1
Application #
8043744
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Rankin, Tracy L
Project Start
2010-04-30
Project End
2011-03-29
Budget Start
2010-04-30
Budget End
2011-03-29
Support Year
10
Fiscal Year
2010
Total Cost
$87,554
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Guo, Wenchang; Liu, Ruiwu; Bhardwaj, Gaurav et al. (2013) CTA095, a novel Etk and Src dual inhibitor, induces apoptosis in prostate cancer cells and overcomes resistance to Src inhibitors. PLoS One 8:e70910
Wang, L-Y; Kung, H-J (2012) Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/CCDH1. Oncogene 31:2907-18
Guo, Wenchang; Liu, Ruiwu; Ono, Yoko et al. (2012) Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs. Mol Pharmacol 82:938-47
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Hsia, Datsun A; Tepper, Clifford G; Pochampalli, Mamata R et al. (2010) KDM8, a H3K36me2 histone demethylase that acts in the cyclin A1 coding region to regulate cancer cell proliferation. Proc Natl Acad Sci U S A 107:9671-6
Wu, Zhaoju; Chang, Pei-Ching; Yang, Joy C et al. (2010) Autophagy Blockade Sensitizes Prostate Cancer Cells towards Src Family Kinase Inhibitors. Genes Cancer 1:40-49
Kung, Hsing-Jien; Evans, Christopher P (2009) Oncogenic activation of androgen receptor. Urol Oncol 27:48-52
Purnell, Phillip R; Mack, Philip C; Tepper, Clifford G et al. (2009) The Src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells. J Thorac Oncol 4:448-54
Kim, Randie H; Bold, Richard J; Kung, Hsing-Jien (2009) ADI, autophagy and apoptosis: metabolic stress as a therapeutic option for prostate cancer. Autophagy 5:567-8

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