Role of alpha6 beta1 Integrin in Prostate Cancer

α6β1整合素在前列腺癌中的作用

• 批准号: 8665532
• 负责人: Cynthia K Miranti
• 金额: $ 7.71万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665532
• 关键词: Adhesions; American; Androgen Receptor; Androgens; Apoptosis; CASP8 and FADD-like apoptosis regulating protein; CD29 Antigen; Cancer Patient; Castration; Cell Adhesion; Cell Culture Techniques; Cell Death; Cell Line; Cell Survival; Cell-Cell Adhesion; Cells; Cessation of life; Chemicals; Clinical Trials; Diagnosis; Disease Resistance; Environment; Epithelial; Epithelial Cells; Exclusion; Extracellular Matrix; Goals; Growth; Human; In Vitro; Integrins; Knowledge; Laboratories; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Modeling; Normal Cell; Nuclear; Nuclear Hormone Receptors; Oncogenes; Outcome Study; PC3 cell line; Pathway interactions; Patients; Phase I Clinical Trials; Preclinical Testing; Prostate; Prostatic Neoplasms; Publishing; Reliance; Resistance; Role; Signal Pathway; Signal Transduction; Steroids; System; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Cell Line; Xenograft procedure; anticancer research; base; effective therapy; human tissue; improved; in vivo; inhibitor/antagonist; innovation; laminin-10; men; mouse model; neoplastic cell; novel; pre-clinical; prostate cancer cell; protein expression; steroid hormone; transcription factor; tumor; virtual

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.

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仍然未知，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雄激素受体（AR）下游的前列腺癌存活途径。促进前列腺癌体内存活的机制，并利用这些知识来测试通过整合素治疗靶向这些存活途径的可行性，这对于前列腺细胞的存活至关重要。 6¿1 优先在前列腺癌中表达，几乎排除其他整合素，并且 ¿1 的程度6¿1 控制前列腺肿瘤中的细胞存活 AR 直接控制的新前列腺癌生存途径尚不清楚。最近鉴定并发表了 6¿1 表达，该途径的功能独立于 PI3K 途径，因此最近鉴定并发表了对 ¿1 表达的抑制。 6¿1 和 PI3K 是有效诱导前列腺癌细胞死亡所必需的，该提案的目的是描述 AR/¿ 6¿11 途径驱动前列腺癌存活并测试联合抑制 ¿ 6¿1 和 PI3K 作为治疗方法的假设是整合素 ¿1 的 AR 依赖性刺激。 NF?B /Bcl-xL/c-FLIP 需要 6¿1 表达来促进前列腺癌细胞的存活，并同时抑制 ¿ 6¿1 和 PI3K 途径是诱导 PI3K 依赖性前列腺癌细胞死亡所必需的。在目标 1 中，表达 AR 的细胞系将用于破译 AR、Erg/Etv 和层粘连蛋白的转录和转录后机制。 -10 控制整合素 ¿ 6¿1 在前列腺癌中的表达 在目标 2 中，表达 AR 的细胞将用于描绘 AR/¿ 下游的特定信号传导途径。 6¿1 控制前列腺癌存活 在目标 3 中，人类组织和细胞系异种移植物将用于测试新的 PI3K 抑制剂 PX866，目前与 ¿1 联合进行 I 期试验。 6¿1 抑制可抑制肿瘤存活和生长，并确定整合素 ¿1 的贡献6¿1 和 PI3K 对肿瘤存活的影响 所提出的研究将显着提高细胞粘附和存活信号传导领域的科学知识，b 描绘核激素受体和整合素 ¿1 之间的新关系背后的机制基础。 6¿1. 通过这些研究，将更深入地了解类固醇和整合素如何合作控制细胞存活，这将进一步了解细胞外基质如何​​影响肿瘤细胞存活。将前列腺特异性 Erg/Etv 融合癌基因与新的 AR/¿ 6¿1 依赖性但 PI3K 独立的生存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改变当前的范例。通过细胞外基质证明 AR 对前列腺肿瘤存活的重要性和贡献。