Role of alpha6 beta1 Integrin in Prostate Cancer

描述（由申请人提供）：雄激素受体（AR）下游促进前列腺癌存活的途径尚不清楚，缺乏知识是前列腺癌治疗进展的关键障碍。本提案的目标是确定促进前列腺癌在体内存活的机制，并利用这些知识来测试治疗靶向这些存活途径的可行性。细胞通过整合素与细胞外基质的粘附对前列腺细胞的存活至关重要。整合素α6ß1在前列腺癌中优先表达而几乎排除其他整合素的机制，以及α6ß1在前列腺肿瘤中控制细胞存活的程度

DESCRIPTION (provided by applicant): 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 α6ß1 is preferentially expressed in prostate cancer, to the virtual exclusion of other integrins, and the extent to which α6ß1controls cell survival in prostate tumors are not known. A new prostate cancer survival pathway in which AR directly controls α6ß1 expression was recently identified and published. This pathway functions independently of the PI3K pathway, such that inhibition of both α6ß1 and PI3K is required to effectively induce prostate cancer cell death. The objective of this proposal is to delineate the mechanisms by which the AR/α6ß1 pathway drives prostate cancer survival and test the feasibility of using combined inhibition of α6ß1 and PI3K as a therapeutic approach. The hypothesis is that AR-dependent stimulation of integrin α6ß1 expression is required for NFκB /Bcl-xL/c-FLIP to promote survival of prostate cancer cells, and simultaneous inhibition of the α6ß1 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 α6ß1 expression in prostate cancer. In Aim 2, AR-expressing cells will be used to delineate the specific signaling pathways downstream of AR/α6ß1 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 α6ß1 inhibition to suppress tumor survival and growth, and determine the contribution of integrin α6ß1 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 α6ß1. 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/α6ß1-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.