Developing therapeutics against resistance to the androgen-deprivation therapy

 描述(申请人提供)：对雄激素剥夺疗法(ADT)的抵抗是前列腺癌(PCA)相关死亡的主要原因。ADT耐药性的潜在机制还不清楚，克服耐药性的策略也没有很好地开发出来，这将在本提案中创新性地解决。YAP和TAZ是转录共激活剂，与包括TEAD1-4在内的转录因子形成复合体，调节其靶基因的表达，控制细胞增殖、凋亡和肿瘤发生。YAP和TAZ以及YAP/TAZ靶基因对ADT反应和PCa进展的影响知之甚少。在这项研究中，我们最初证明雄激素不敏感的PCa细胞中的TAZ水平和活性高于雄激素敏感的PCa细胞，ADT上调TAZ的水平和活性、Ax1受体酪氨酸激酶(RTK)和Tie2 RTK的配体血管生成素-1(Angpt1)的水平。此外，敲除TAZ而不是YAP会使PCa细胞对ADT的反应敏感，一个结构性活性(CA)TAZ突变体TAZ-S89A赋予ADT抗性，而Ax1抑制剂和Angpt1-Tie2抑制剂则敏化PCa细胞的ADT反应。此外，我们还发现，TAZ上调了Angpt1和ADAM 8的表达，Angpt1促进了Tie2的激活，ADAM8促进了Ax1的切割/脱落，导致了非配体依赖的Ax1激活。我们将检验一个新的假设，即TAZ在促进PCa的ADT抵抗中起关键作用，并且TAZ通过分别以TEAD2/4和ADAM8依赖的方式上调和激活Ax1，以及通过上调Angpt1增强Angpt1-Tie2功能轴的活性来诱导ADT抵抗。我们进一步假设，抑制TAZ活性和/或联合抑制Ax1脱发/活性和Angpt1-Tie2活性是敏化PCa的ADT反应和阻断PCA进展的新途径。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抵抗。目的2确定Angpt1-Tie2功能轴在TAZ诱导的ADT抵抗中的作用。目的3确定抑制TAZ活性、联合抑制Angpt1-Tie2活性和Ax1脱落/活性是克服前列腺癌ADT耐药的新途径。所获得的结果将确定TAZ和TAZ效应器Ax1、ADAM8和Angpt1是导致ADT耐药的新的分子决定因素，它们可以作为新的治疗靶点。此外，这一提议的完成将导致TAZ、Ax1/ADMA8和Angpt1/Tie2活性的新型抑制剂的开发，以及这些抑制剂的新组合来敏化PCA的ADT反应。因此，这项建议意义重大。

 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.