Role of alpha6 beta1 Integrin in Prostate Cancer

描述(申请人提供)：雄激素受体(AR)下游促进前列腺癌存活的途径仍不清楚，缺乏知识是前列腺癌治疗进展的关键障碍。这项建议的目标是确定促进前列腺癌在体内存活的机制，并利用这一知识来测试以这些存活途径为靶点的治疗的可行性。细胞通过整合素与细胞外基质的黏附对前列腺细胞的存活至关重要。整合素在前列腺癌中优先表达的机制，以及整合素在前列腺癌中控制细胞存活的程度 都是未知的。最近发现并发表了一种新的前列腺癌生存途径，其中AR直接控制6‘1的表达。该途径独立于PI3K途径发挥作用，因此需要同时抑制PI3K和PI3K才能有效地诱导前列腺癌细胞死亡。本研究的目的是阐明AR/6？11通路促进前列腺癌生存的机制，并测试联合应用抑制6？1和PI3K作为治疗方法的可行性。该假说认为，依赖AR刺激整合素6？1的表达是促进前列腺癌细胞存活所必需的，而同时抑制整合素6？1和PI3K通路则是诱导依赖PI3K的前列腺癌细胞死亡的必要条件。在目标1中，AR表达的细胞系将被用来破译AR、Erg/ETV和Laminin-10调控前列腺癌整合素6？1表达的转录和转录后机制。在目标2中，AR表达细胞将被用来描绘AR/6下游控制前列腺癌生存的特定信号通路。在目标3中，将使用人体组织和细胞系异种移植来测试一种新的PI3K抑制剂PX866，该抑制剂目前处于I期试验，与抑制肿瘤存活和生长的药物联合使用，并确定整合素6和PI3K在体内对肿瘤存活的贡献。这些研究将显著提高细胞黏附和生存信号领域的科学知识，阐明核激素受体和整合素之间新的关系背后的机制基础。通过这些研究，我们将更深入地了解类固醇和整合素是如何合作控制细胞生存的，这将进一步加深我们对细胞外基质如何影响肿瘤细胞生存的了解。前列腺癌领域将通过将前列腺特异性ERG/ETV融合癌基因与一种新的依赖于AR/β6，但不依赖于PI3K的生存途径联系起来，这可能是治疗前列腺癌患者策略的一部分。在人类患者异种移植中评估这一途径将有助于确定在体内靶向这些途径的可行性，并通过证明AR通过细胞外基质对前列腺癌生存的重要性和贡献来改变目前的研究范式。

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 ¿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.