Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs

抗凋亡的BCL2家族蛋白(包括BCL2、BCLXL和MCL1)通过中和Bax和BAK发挥作用， 并通过抑制仅有BH3的促凋亡蛋白来激活Bax/BAK。BH3-模拟物是一种药物 通过结合和抑制bcl2、bclxl或mcl1促进细胞凋亡。Navitoclax抑制BCL2和BCLXL 在血液系统恶性肿瘤中具有单药活性，但由于BCLXL而导致血小板减少 抑制力。一种BCL2特异性的BH3模拟物，可以节省血小板，ventoclax，具有类似的活性，并得到FDA的批准 治疗几种血液系统恶性肿瘤。不幸的是，这些目前临床上可用的BH3模拟物已经 在大多数实体肿瘤中，单一药物活性有限，这似乎实质上反映了MCL1的更大作用。 抑制MCL1的BH3模拟药物最近被开发出来，并处于早期试验阶段，但仍处于临床前 我们和其他人的研究表明，在大多数情况下，有必要同时抑制BCLXL和MCL1 实现强大的凋亡反应，毒性可能会限制bcl2/bclxl和bcl2/bclxl结合的能力 MCL1抑制剂在患者中的应用。尽管BH3模拟物在PC中作为单一药物的疗效有限，但它们可能 基因组改变影响细胞凋亡途径的PC亚群中的活性。我们最近确定了 线粒体泛素连接酶March5作为细胞应激反应中MCL1降解的主要中介， 并发现在高达~5%的CRPC中发生的March5基因缺失可以对BH3模拟药物敏感。 其他增加MCL1表达的改变(包括MCL1基因扩增)在PC中也很常见 并可增加对MCL1的依赖。相反，我们的初步数据表明，具有 BRCA2/RB1缺失可能与BCLXL高度相关。在这些数据的基础上，目标1是确定和描述 基因组改变可作为单一药物BH3模拟疗法临床试验的可靠生物标记物。 虽然PC的一个子集可能对单一的BH3模拟药物有反应，但完全利用这些药物将 可能需要确定协同联合疗法。事实上，我们之前已经确定了一个 可显著促进MCL1降解并对Navitoclax增敏的现有药物数量。因此， 目标2是确定利用BH3模拟剂来驱动CRPC细胞凋亡反应的联合疗法。 最后，我们假设去势敏感的前列腺癌(CSPC)细胞暴露于高强度的雄激素 信号抑制可能具有降低的凋亡阈值，并容易受到添加的影响，至少是暂时的 一种类似BH3的药物。因此，Aim 2还将决定是否可以使用BH3模拟来利用 CSPC中密集的ASI尖锐地生成了漏洞。总体而言，我们假设BH3模拟药物将 在基因定义的CRPC子集中高度有效，并更广泛地与其他目标组合 探员们。具体目标是1)确定前列腺癌中对BH3模拟物敏感的基因组变化 药物和2)确定对前列腺癌有效的BH3模拟联合疗法

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