The pathways that promote prostate cancer survival downstream of the androgen receptor (AR) remain unknown and that lack of knowledge is a critical barrier to the progress of treating prostate cancer. The goal of this proposal is to determine the mechanisms which promote prostate cancer survival in vivo and use this knowledge to test the feasibility of therapeutically targeting those survival pathways. Cell adhesion to extracellular matrix via integrins is critical for the survival of prostate cells. The mechanism by which integrin ?6?1is preferentially expressed in prostate cancer, to the virtual exclusion of other integrins, and the extent to which ?6?1controls cell survival in prostate tumors are not known. A new prostate cancer survival pathway in which AR directly controls ?6?1expression was recently identified and published. This pathway functions independently of the PI3K pathway, such that inhibition of both ?6?1and PI3K is required to effectively induce prostate cancer cell death. The objective of this proposal is to delineate the mechanisms by which the AR/ ?6?11 pathway drives prostate cancer survival and test the feasibility of using combined inhibition of ?6?1 and PI3K as a therapeutic approach. The hypothesis is that AR-dependent stimulation of integrin ?6?1 expression is required for NF?B /Bcl-xL/c-FLIP to promote survival of prostate cancer cells, and simultaneous inhibition of the ?6?1 and PI3K pathways is required to induce death of PI3K-dependent prostate cancer cells.
In Aim 1, AR-expressing cell lines will be used to decipher the transcriptional and post-transcriptional mechanisms by which AR, Erg/Etv, and laminin-10 control integrin ?6?1 expression in prostate cancer.
In Aim 2, AR-expressing cells will be used to delineate the specific signaling pathways downstream of AR/ ?6?1 that control prostate cancer survival.
In Aim 3, human tissue and cell line xenografts will be used to test a new PI3K inhibitor, PX866, currently in phase I trials in combination with ?6?1 inhibition to suppress tumor survival and growth, and determine the contribution of integrin ?6?1 and PI3K to tumor survival in vivo. The proposed studies will significantly improve scientific knowledge in the fields of cell adhesion and survival signaling, b delineating the mechanistic basis behind a novel relationship between a nuclear hormone receptor and integrin ?6?1. Through these studies a more in-depth understanding of how steroids and integrins cooperate to control cell survival will be gained, which will further our knowledge of how the extracellular matrix impacts tumor cell survival. The prostate cancer field will be advanced by linking the prostate-specific Erg/Etv fusion oncogenes with a new AR/ ?6?1-dependent, but PI3K-independent, survival pathway that could be part of a strategy for treating prostate cancer patients. Assessment of this pathway in human patient xenografts will help to determine the feasibility of targeting these pathways in vivo and shift current paradigms by demonstrating the importance and contribution of AR to prostate tumor survival through the extracellular matrix.
