Prostate Cancer (CaP) is the second leading cause of cancer deaths in American men. It has been demonstrated that CaP cells undergo neuroendocrine differentiation (NED) in response to various stimuli in the CaP environment. NED is suggested to correlate with progression and worsened outcome of CaP. We propose to study how NED effects the growth and migration of CaP cells both in vitro and in vivo. Additionally, we will delineate the non-receptor tyrosine kinase signaling mechanisms responsible for these events. To achieve this, we propose two specific aims: 1)To demonstrate that neurotrophins promote the biological aggressiveness of CaP. We will induce NED in CaP cells and study their androgen-independent and anchorage-independent growth. We will study both autocrine and paracrine effects of these events. Similarly, we will study the effects of NED on CaP cell migration. These experiments will be performed using exogenous neurotrophins as well as stably transfected CaP cell lines to be established. Furthermore, we will study these events in vivo to demonstrate biological relevance. 2)To determine the molecular involvement of non-receptor tyrosine kinases in neurotrophin mediated progression of CaP to the aggressive phenotype. Using a variety of signal transduction molecule constructs, we will delineate the non-receptor tyrosine kinase pathways contributing to the enhanced growth and migration of CaP cells in the NED state. Specifically, we will focus on Src, FAC and Etk as supported by our preliminary data. These non-receptor tyrosine kinasess are attractive therapeutic targets for inhibiting the enhanced biological aggressiveness of CaP in the NEd state. This Mentored Clinical Scientist proposal merges the Mentor's strong background in tyrosine kinases with the applicant's previous experience in invasion and metastases to provide the applicant with a new area of skills and expertise. This proposal is based on significant preliminary data and has strong translational potential for future proposals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK060748-05
Application #
6990595
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Moen, Laura K
Project Start
2002-03-01
Project End
2006-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$121,770
Indirect Cost
Name
University of California Davis
Department
Urology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Chang, Y-M; Bai, L; Liu, S et al. (2008) Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene 27:6365-75
Nelson, E C; Cambio, A J; Yang, J C et al. (2007) Clinical implications of neuroendocrine differentiation in prostate cancer. Prostate Cancer Prostatic Dis 10:6-14
Nelson, Eric C; Cambio, Angelo J; Yang, Joy C et al. (2007) Biologic agents as adjunctive therapy for prostate cancer: a rationale for use with androgen deprivation. Nat Clin Pract Urol 4:82-94
Lee, Li-Fen; Louie, Maggie C; Desai, Sonal J et al. (2004) Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene 23:2197-205
Busby, J E; Shih, S-J; Yang, J C et al. (2003) Angiogenesis is not mediated by prostate cancer neuropeptides. Angiogenesis 6:289-93