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.
