Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs

前列腺癌对 BH3 模拟药物的脆弱性

• 批准号: 10279279
• 负责人: Steven P. Balk
• 金额: $ 40.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10279279
• 关键词: Acute; Affect; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Automobile Driving; BAX gene; BCL2 gene; BCL2L1 gene; BCL2L11 gene; BRCA2 gene; Binding; Biological Markers; Blood Platelets; Castration; Cellular Stress; Clinical; Clinical Trials; Combined Modality Therapy; DNA Sequence Alteration; Data; Dependence; Exposure to; FDA approved; Gene Amplification; Gene Deletion; Hematologic Neoplasms; MCL1 gene; Malignant neoplasm of prostate; Mediator of activation protein; Medical Castration; Metastatic Prostate Cancer; Mitochondria; Modeling; Pathway interactions; Patients; Pharmaceutical Preparations; Protein Family; Proteins; RB1 gene; Recurrence; Role; Signal Transduction; Solid Neoplasm; Thrombocytopenia; Toxic effect; VCaP; androgen deprivation therapy; base; castration resistant prostate cancer; in vivo; inhibitor/antagonist; mimetics; preclinical study; pro-apoptotic protein; prostate cancer cell; response; standard care; targeted agent; tumor; ubiquitin ligase

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

抗凋亡 BCL2 家族蛋白（包括 BCL2、BCLXL 和 MCL1）通过中和 BAX 和 BAK 发挥作用， 并通过抑制可激活 BAX/BAK 的 BH3 促凋亡蛋白。 BH3-模拟物是这样的药物 通过结合并抑制 BCL2、BCLXL 或 MCL1 来增强细胞凋亡。 Navitoclax 抑制 BCL2 和 BCLXL 对血液系统恶性肿瘤具有单药活性，但会因 BCLXL 导致血小板减少症 抑制。一种可以保护血小板的 BCL2 特异性 BH3 模拟物 Venetoclax 具有类似的活性，并已获得 FDA 批准 用于多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 在大多数实体瘤中，单药活性有限，这似乎实质上反映了 MCL1 的更大作用。 抑制 MCL1 的 BH3 模拟药物最近已被开发出来并处于早期试验中，但临床前 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 实现强大的细胞凋亡反应，并且毒性很可能会限制 BCL2/BCLXL 与 BCL2/BCLXL 结合的能力 患者中的 MCL1 抑制剂。尽管 BH3 模拟物作为单一药物治疗 PC 的疗效有限，但它们可能具有 PC亚群的活性与影响细胞凋亡途径的基因组改变。我们最近确定了 线粒体泛素连接酶 MARCH5 作为响应细胞应激的 MCL1 降解的主要介质， 并发现大约 5% 的 CRPC 中发生的 MARCH5 基因缺失可以使 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 并且可以增加 MCL1 依赖性。相反，我们的初步数据表明，具有 BRCA2/RB1 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 基因组改变可用作单药 BH3 模拟疗法临床试验的稳健生物标志物。 虽然 PC 的一个子集可能对单剂 BH3 模拟药物有反应，但充分利用这些药物将 可能需要确定协同联合疗法。事实上，我们之前已经确定了 许多可用药物可以显着增强 MCL1 降解并使 navitoclax 敏感。所以， 目标 2 是确定利用 BH3 模拟药物驱动 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）细胞暴露于强雄激素 信号传导抑制可能会降低细胞凋亡阈值，并且容易受到添加的影响，至少是暂时的 BH3模拟药物。因此，目标 2 还将确定 BH3 模拟物是否可用于利用 CSPC 中密集的 ASI 严重产生的漏洞。总的来说，我们假设 BH3 模拟药物将 对基因定义的 CRPC 的子集非常有效，并且更广泛地与其他目标组合 代理。具体目标是 1) 鉴定前列腺癌中对 BH3 模拟物敏感的基因组改变 药物和 2) 确定对前列腺癌有效的 BH3 模拟联合疗法