Role of alpha6 beta1 Integrin in Prostate Cancer

描述（由申请人提供）：促进雄激素受体（AR）下游前列腺癌生存的途径仍然未知，缺乏知识是前列腺癌治疗进展的关键障碍。该提案的目标是确定促进前列腺癌体内存活的机制，并使用这些知识来测试治疗靶向这些存活途径的可行性。细胞通过整合素粘附到细胞外基质对于前列腺细胞的存活至关重要。整合素α 6 β 1在前列腺癌中优先表达的机制，以及α 6 β 1在前列腺肿瘤中控制细胞存活的程度 不知道。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α 6 β 1表达。该途径独立于PI 3 K途径发挥作用，因此需要抑制α 6 β 1和PI 3 K以有效诱导前列腺癌细胞死亡。本提案的目的是描述AR/α 6 β 1通路驱动前列腺癌存活的机制，并测试使用α 6 β 1和PI 3 K的联合抑制作为治疗方法的可行性。该假说认为，NFκB /Bcl-xL/c-FLIP促进前列腺癌细胞存活需要AR依赖性刺激整联蛋白α 6 β 1表达，同时抑制α 6 β 1和PI 3 K途径诱导PI 3 K依赖性前列腺癌细胞死亡。在目的1中，AR表达细胞系将用于破译AR、Erg/Etv和层粘连蛋白-10控制前列腺癌中整合素α 6 β 1表达的转录和转录后机制。在目标2中，AR表达细胞将用于描绘AR下游的特异性信号传导途径。 AR/α 6 β 1控制前列腺癌生存。在目标3中，将使用人组织和细胞系异种移植物来测试新的PI 3 K抑制剂PX 866，其目前在I期试验中与α 6 β 1抑制剂组合以抑制肿瘤存活和生长，并确定整合素α 6 β 1和PI 3 K对体内肿瘤存活的贡献。所提出的研究将显著提高细胞粘附和存活信号传导领域的科学知识，B描绘了核激素受体和整合素α 6 β 1之间新关系背后的机制基础。通过这些研究，将获得对类固醇和整合素如何合作控制细胞存活的更深入的了解，这将进一步加深我们对细胞外基质如何影响肿瘤细胞存活的认识。通过将前列腺特异性Erg/Etv融合癌基因与一种新的AR/α 6 β 1依赖性、但PI 3 K独立性的生存途径联系起来，前列腺癌领域将得到推进，该途径可能成为治疗前列腺癌患者策略的一部分。在人类患者异种移植物中评估该途径将有助于确定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肿瘤存活的重要性和贡献来改变当前的范式。

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 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.