Developing therapeutics against resistance to the androgen-deprivation therapy

 描述（由申请方提供）：雄激素剥夺治疗（ADT）抵抗是前列腺癌（PCa）相关死亡的主要原因。ADT耐药的机制尚不清楚，克服耐药的策略尚未得到很好的开发，这将在本提案中创新性地解决。雅普和TAZ是转录共激活因子，并与包括TEAD 1 -4在内的转录因子形成复合物，以调节其控制细胞增殖、凋亡和肿瘤发生的靶基因的表达。关于雅普和TAZ以及雅普/TAZ靶基因对ADT反应和PCa进展的影响知之甚少。我们最初在该提议中证明，与雄激素敏感的PCa细胞相比，雄激素不敏感的PCa细胞中的TAZ水平和活性更高，并且ADT上调TAZ的水平和活性、AXL受体酪氨酸激酶（RTK）和血管生成素-1（Angpt 1）（Tie 2 RTK的配体）的水平。此外，敲低TAZ而非雅普可使PCa细胞对ADT的反应敏感，并且组成型活性（CA）TAZ突变体TAZ-S89 A赋予ADT抗性，而AXL抑制剂和Angpt 1-Tie 2抑制剂使PCa细胞的ADT反应敏感。此外，我们发现TAZ上调Angpt 1和ADAM 8表达，Angpt 1促进Tie 2活化，ADAM 8促进AXL切割/脱落，导致配体非依赖性AXL活化。我们将测试一个新的假设，即TAZ在促进PCa的ADT抗性中起关键作用，并且TAZ分别以TEAD 2/4和ADAM 8依赖性方式通过上调和激活AXL诱导ADT抗性;以及通过上调Angpt 1增强Angpt 1-Tie 2功能轴的活性。我们进一步假设，抑制TAZ活性和/或联合抑制AXL脱落/活性和Angpt 1-Tie 2活性是使PCa的ADT反应增敏和阻断PCa进展的新方法。提出了三个具体目标。目的1是确定TAZ通过或部分通过AXL促进ADT抗性。目的2是确定Angpt 1-Tie 2功能轴对TAZ诱导的ADT抗性的贡献。目的3：建立TAZ活性抑制和Angpt 1-Tie 2活性和AXL脱落/活性的联合抑制是克服PCa ADT抗性的新方法。所获得的结果将确立TAZ和TAZ效应子AXL、ADAM 8和Angpt 1是ADT耐药的新分子决定因素，并且它们可作为新的治疗靶点。此外，这一提议的完成将导致开发TAZ、AXL/ADMA 8和Angpt 1/Tie 2活性的新型抑制剂以及这些抑制剂的新型组合以敏化PCa的ADT反应。因此，这项建议是非常重要的。

 DESCRIPTION (provided by applicant): Resistance to the androgen-deprivation therapy (ADT) is the major cause of prostate cancer (PCa)- related death. Mechanisms underlying the ADT resistance are not well understood and the strategies for overcoming the resistance have not been well developed, which will be addressed innovatively in this proposal. YAP and TAZ are transcription co-activators and form complexes with transcription factors including TEAD1-4 to regulate expression of their target genes that control cell proliferation, apoptosis, and tumorigenesis. Little is known about the effects of YAP and TAZ and the YAP/TAZ target genes on the ADT responses and the PCa progression. We demonstrate originally in this proposal that TAZ level and activity are higher in the androgen-insensitive compared to the androgen- sensitive PCa cells and that the ADT up-regulates the level and activity of TAZ, Levels of AXL receptor tyrosine kinase (RTK) and angiopoietin-1 (Angpt1), a ligand of Tie2 RTK. In addition, knockdown of TAZ but not YAP sensitizes the PCa cell response to the ADT and a constitutively active (CA) TAZ mutant, TAZ-S89A, confers the ADT resistance whereas an AXL inhibitor and the Angpt1-Tie2 inhibitors sensitize the ADT response of PCa cells. Furthermore, we show that TAZ up- regulates Angpt1 and ADAM 8 expression and that Angpt1 promotes Tie2 activation and ADAM8 promotes AXL cleavage/shedding, resulting in the ligand-independent AXL activation. We will test a novel hypothesis that TAZ plays a key role in promoting the ADT resistance of PCa and that TAZ induces the ADT resistance by up-regulating and activating AXL in the TEAD2/4 and ADAM8 dependent manner, respectively; and by enhancing activity of the Angpt1-Tie2 functional axis through up-regulating Angpt1. We further hypothesize that inhibition of TAZ activity and/or combinational inhibition of the AXL shedding/activity and the Angpt1-Tie2 activity are novel approaches for sensitizing the ADT response of PCa and blocking the PCa progression. Three specific aims are proposed. Aim 1 is to establish that TAZ promotes the ADT resistance through or partially through AXL. Aim 2 is to determine the contribution of the Angpt1-Tie2 functional axis to the TAZ-induced ADT resistance. Aim 3 is to establish that inhibition of TAZ activity and combinational inhibition of the Angpt1-Tie2 activity and the AXL shedding/activity are novel approaches to overcome the ADT resistance of PCa. Results obtained will establish that TAZ and the TAZ effectors, AXL, ADAM8, and Angpt1, are the novel molecular determinants underlying the ADT resistance and they serve as novel therapeutic targets. Furthermore, accomplishment of this proposal will lead to development of the novel inhibitors of TAZ, AXL/ADMA8, and Angpt1/Tie2 activities and the novel combinations of these inhibitors to sensitize the ADT response of PCa. Therefore, this proposal is highly significant.