Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs

抗凋亡BCL 2家族蛋白（包括BCL 2、BCL XL和MCL 1）通过中和BAX和巴克起作用， 以及通过抑制可激活BAX/巴克的仅BH 3促凋亡蛋白。BH 3-模拟物是 通过结合并抑制BCL 2、BCL XL或MCL 1来增强细胞凋亡。Navitoclax抑制BCL 2和BCLXL 并且在血液恶性肿瘤中具有单药活性，但由于BCLXL而引起血小板减少症 抑制作用一种BCL-2特异性BH 3模拟物，可以减少血小板，维奈托克，具有类似的活性，并获得FDA批准。 几种恶性血液病的治疗方法不幸的是，这些目前临床上可获得的BH 3-模拟物 在大多数实体瘤中，单一药物活性有限，这似乎基本上反映了MCL 1的更大作用。 抑制MCL 1的BH 3模拟药物最近已经开发出来，并处于早期试验中，但处于临床前阶段。 我们和其他人的研究表明，在大多数情况下，抑制BCLXL和MCL 1是必要的， 实现强有力的凋亡应答，并且毒性可能会限制联合收割机BCL 2/BCL XL和BCL 2/BCL XL的结合能力。 患者中的MCL 1抑制剂。尽管BH 3模拟物作为单一药剂在PC中具有有限的功效，但它们可能具有更好的治疗效果。 在具有影响凋亡途径的基因组改变的PC亚群中的活性。我们最近发现 线粒体泛素连接酶MARCH 5作为响应细胞应激的主要介质MCL 1降解， 并发现在高达~5%的CRPC中发生的MARCH 5基因缺失可以对BH 3模拟药物敏感。 增加MCL 1表达的其他改变（包括MCL 1基因扩增）在PC中也很常见 并且可以赋予增加的MCL 1依赖性。相反，我们的初步数据表明， BRCA 2/RB 1丢失可能高度依赖于BCLXL。基于这些数据，目标1是识别和表征 这些基因组改变可用作单一药剂BH 3模拟疗法的临床试验的稳健生物标志物。 虽然PC的一个子集可能对单一药剂BH 3模拟药物有反应，但充分利用这些药物将使 可能需要鉴定协同组合疗法。事实上，我们以前已经确定了一个 许多可用的药物，可以显着提高MCL 1降解和敏感navitoclax。因此，我们认为， 目的2是鉴定利用BH 3模拟剂驱动CRPC中的凋亡反应的组合疗法。 最后，我们假设去势敏感性前列腺癌（CSPC）细胞暴露于强雄激素， 信号传导抑制可能具有降低的细胞凋亡阈值，并且至少是暂时地易受添加 一种BH 3模拟药物因此，目标2还将确定BH 3模拟物是否可用于开发 CSPC中密集的ASI严重产生的漏洞。总的来说，我们假设BH 3模拟药物 在基因定义的CRPC亚组中高度有效，并且更广泛地与其他靶向药物组合 剂.具体目的是1）鉴定前列腺癌中对BH 3模拟物敏感的基因组改变 2）鉴定在前列腺癌中有效的BH 3模拟物组合疗法

The anti-apoptotic BCL2 family proteins (including BCL2, BCLXL, and MCL1) act by neutralizing BAX and BAK, and by inhibiting the BH3-only pro-apoptotic proteins that can activate BAX/BAK. BH3-mimetics are drugs that enhance apoptosis by binding to and inhibiting BCL2, BCLXL, or MCL1. Navitoclax inhibits BCL2 and BCLXL and has single-agent activity in hematological malignancies, but causes thrombocytopenia due to BCLXL inhibition. A BCL2-specific BH3-mimetic that spares platelets, venetoclax, is similarly active and FDA approved for several hematological malignancies. Unfortunately, these currently clinically available BH3-mimetics have limited single agent activity in most solid tumors, which appears to substantially reflect a greater role for MCL1. BH3 mimetic drugs that inhibit MCL1 have more recently been developed and are in early trials, but preclinical studies from us and others suggest that it will in most cases be necessary to inhibit both BCLXL and MCL1 to achieve robust apoptotic responses, and it is likely that toxicity will limit the ability to combine BCL2/BCLXL and MCL1 inhibitors in patients. Although BH3 mimetics have limited efficacy as single agents in PC, they may have activity in subsets of PC with genomic alterations affecting apoptotic pathways. We recently identified the mitochondrial ubiquitin ligase MARCH5 as the primary mediator MCL1 degradation in response to cellular stress, and found that MARCH5 gene deletion that occurs in up to ~5% of CRPC can sensitize to BH3 mimetic drugs. Other alterations that increase MCL1 expression (including MCL1 gene amplification) are also frequent in PC and can confer increased MCL1 dependence. Conversely, our preliminary data indicate that PC with BRCA2/RB1 loss may be highly dependent on BCLXL. Based on these data, Aim 1 is to identify and characterize genomic alterations that may be used as robust biomarkers for clinical trials of single agent BH3 mimetic therapy. While a subset of PC may be responsive to single agent BH3 mimetic drugs, fully exploiting these drugs will likely require the identification of synergistic combination therapies. Indeed, we have previously identified a number of available drugs that can markedly enhance MCL1 degradation and sensitize to navitoclax. Therefore, Aim 2 is to identify combination therapies that exploit BH3 mimetic agents to drive apoptotic responses in CRPC. Finally, we hypothesize that castration-sensitive prostate cancer (CSPC) cells exposed to intensive androgen signaling inhibition may have a reduced apoptotic threshold and be vulnerable, at least transiently, to the addition of a BH3 mimetic drug. Therefore, Aim 2 will also determine whether BH3 mimetics can be used to exploit vulnerabilities generated acutely by intensive ASI in CSPC. Overall, we hypothesize that BH3 mimetic drugs will be highly effective in a subset of genetically defined CRPCs, and more broadly in combination with other targeted agents. The Specific Aims are 1) Identify genomic alterations in prostate cancer that sensitize to BH3 mimetic drugs and 2) Identify BH3 mimetic combination therapies that are effective in prostate cancer