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来起作用， 并通过抑制可以激活BAX/BAK的仅BH3促凋亡蛋白。 Bh3-Mimetics是药物 通过结合并抑制BCL2，BCLXL或MCL1来增强凋亡。 Navitoclax抑制BCL2和BCLXL 并具有血液学恶性肿瘤的单药活性，但由于BCLXL引起的血小板减少症 抑制。 BCl2特异性的BH3模拟省剂，可避免血小板，venetoclax，同样活跃，并且批准了FDA 对于几种血液学恶性肿瘤。不幸的是，这些当前可用的BH3-Mimetics具有 在大多数实体瘤中的单一药物活性有限，这似乎反映出MCL1的作用更大。 最近开发了抑制MCL1的BH3模拟药物，正在早期试验中，但临床前进行 我们和其他人的研究表明，在大多数情况下，抑制BCLXL和MCL1的必要 实现强大的凋亡反应，毒性可能会限制结合Bcl2/bclxl和 患者的MCL1抑制剂。尽管BH3 Mimetics作为PC中的单个代理的功效有限，但它们可能具有 在PC的子集中活性，其基因组改变影响凋亡途径。我们最近确定了 线粒体泛素连接酶三月5作为响应细胞应激的主要介体MCL1降解， 并发现在高达约5％的CRPC中发生的March5基因缺失可以对BH3模拟药物敏感。 在PC中，其他增加MCL1表达（包括MCL1基因扩增）的变化也很频繁 并可以赋予MCL1依赖性增加。相反，我们的初步数据表明PC带有 BRCA2/RB1损失可能高度依赖于BCLXL。基于这些数据，目标1是识别和表征 可以用作单一药物BH3模拟疗法的临床试验的鲁棒生物标志物的基因组改变。 虽然一部分PC可能对单药BH3模拟药物有反应，但充分利用这些药物会 可能需要鉴定协同组合疗法。确实，我们以前已经确定了 可显着增强MCL1降解并敏感到Navitoclax的可用药物数量。所以， AIM 2是确定利用BH3模拟剂来驱动CRPC中凋亡反应的组合疗法。 最后，我们假设castration敏感的前列腺癌（CSPC）细胞暴露于密集的雄激素 信号抑制可能会降低凋亡阈值，并且至少瞬间易受伤害 BH3模拟药物。因此，AIM 2还将确定是否可以使用BH3模拟物来利用 CSPC中密集的ASI急性产生的脆弱性。总体而言，我们假设BH3模拟药物将 在遗传定义的CRPC的一部分中非常有效，并且更广泛地与其他目标结合 代理商。具体目的是1）确定前列腺癌中的基因组改变，该癌对BH3模拟敏感 药物和2）鉴定有效的前列腺癌的BH3模拟组合疗法