A New Strategy to Increase Proteotoxic Cell Death in Hepatocellular Carcinoma

增加肝细胞癌中蛋白毒性细胞死亡的新策略

• 批准号: 10330604
• 负责人: CARLOS M PEREZ-STABLE
• 金额: $ 6.36万
• 依托单位: SOUTH FLORIDA VA FDN/RESEARCH/ EDUCATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330604
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; Autophagocytosis; BCL2 gene; Carcinogens; Cell Death; Cellular Stress; Clinical; Clinical Trials; Combined Modality Therapy; Cyclophilins; Cyclosporine; Data; Drug Combinations; Family; Generations; Goals; Growth; High Fat Diet; Histone Deacetylase; Histone Deacetylase Inhibitor; Link; Liver Fibrosis; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Multiple Myeloma; Mus; Normal Cell; Normal tissue morphology; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Primary carcinoma of the liver cells; Protein Biosynthesis; Proteins; Quality of life; Role; Solid; Solid Neoplasm; Stress; System; Testing; Tissues; Toxic effect; Ubiquitin; Validation; Viral; Xenograft procedure; analog; biological adaptation to stress; cancer cell; chemotherapy; clinically relevant; fibrosing agent; improved; inhibitor; innovation; liver cancer model; misfolded protein; mouse model; multicatalytic endopeptidase complex; novel; protein folding; proteotoxicity; response; side effect; success; treatment strategy; tumor; tumor growth; tumor xenograft

Inhibitors of the ubiquitin proteasome system (UPS, the major pathway that degrades unfolded proteins) increase proteotoxic stress and have clinical success for multiple myeloma but not for solid cancers such as hepatocellular carcinoma (HCC). Current clinical strategies to further enhance proteotoxic stress in solid tumors by combining pan-histone deacetylase (HDAC) + UPS inhibitors has some success but comes with high toxicity to normal tissues. We propose an alternative strategy to enhance proteotoxic stress in HCC but with less toxicity to non-cancer cells by combining a new pan-cyclophilin inhibitor CRV431 (CRV) and a second-generation UPS inhibitor ixazomib (Ixz). Since cyclophilins are important in protein folding, combining a pan-cyclophilin inhibitor such as CRV to increase misfolded proteins and blocking their degradation with a UPS inhibitor such as Ixz amplifies proteotoxic stress and forces apoptotic cell death. Our preliminary data supports the use of CRV + Ixz as a new strategy for treatment of HCC without causing toxicity to non-cancer cells. We propose that maintenance of elevated levels of pro-survival response mediator XBP1s (unfolded protein response) and low cyclophilin expression/activity triggers cell death in HCC cells. Notably, CRV + Ixz is not toxic in a non-cancer compared to HCC cells whereas a current proteotoxic stress combination Panobinostat (clinically relevant pan-HDAC inhibitor) + Ixz is equally toxic in non-cancer and HCC cells. The hypothesis of this proposal is that CRV + Ixz maintenance of high XBP1s and low cyclophilin expression/activity overwhelms pro-survival pathways and forces HCC cells toward apoptotic cell death without harming normal cells. The rationale is that if this new combination kills HCC cells without harming normal cells in preclinical models, the chances for success in clinical settings will increase. Aim 1: Identify mediators that link activation of apoptotic cell death in CRV + Ixz treated HCC but not in non- cancer cells. Aim 2: Investigate the efficacy of the orally bioavailable CRV + Ixz combination in mouse models of HCC. In advanced HCC, there has been little progress in discovering new chemotherapy strategies. We propose that targeting the essential proteotoxic stress response survival pathway by combining orally bioavailable pan-cyclophilin and UPS inhibitors will be a useful strategy to selectively kill HCC without causing excessive side effects to normal tissues. Currently, CRV is being investigated as an anti-viral and anti-liver fibrosis agent and we are the first to propose its use in HCC combination therapy. The long-term goal will be to use CRV + Ixz to treat HCC patients with the hope that proteotoxic stress cell death specifically in HCC cells without causing toxicity to normal tissues will increase overall survival and improve quality of life.

泛素蛋白酶体系统（UPS，降解未折叠蛋白的主要途径）的抑制剂 增加蛋白毒性应激，并对多发性骨髓瘤有临床成功，但对实体癌如 肝细胞癌（HCC）。目前的临床策略，以进一步提高蛋白毒性应激在固体 通过组合泛组蛋白去乙酰化酶（HDAC）+ UPS抑制剂治疗肿瘤取得了一些成功，但伴随着 对正常组织毒性高。我们提出了一种替代策略来增强HCC中的蛋白毒性应激， 通过组合新的泛亲环蛋白抑制剂CRV 431（CRV）和 第二代UPS抑制剂ixazomib（Ixz）。由于亲环蛋白在蛋白质折叠中很重要，因此将亲环蛋白结合到蛋白质折叠中是必要的。 泛亲环蛋白抑制剂，如CRV，以增加错误折叠的蛋白质，并用UPS阻断其降解 抑制剂如Ixz放大蛋白毒性应激并迫使凋亡细胞死亡。 我们的初步数据支持使用CRV + Ixz作为治疗HCC的新策略， 对非癌细胞产生毒性。我们认为维持高水平的促生存反应 介体XBP 1 s（未折叠蛋白反应）和亲环蛋白表达/活性降低触发HCC中的细胞死亡 细胞值得注意的是，与HCC细胞相比，CRV + Ixz在非癌细胞中是无毒的，而目前的蛋白毒性的CRV + Ixz在非癌细胞中是无毒的。 应激组合帕比司他（临床相关泛HDAC抑制剂）+ Ixz在非癌症中具有相同毒性 和HCC细胞。 该提议的假设是CRV + Ixz维持高XBP 1和亲环蛋白低水平 表达/活性破坏促存活途径并迫使HCC细胞向凋亡细胞方向发展 不伤害正常细胞。基本原理是，如果这种新的组合杀死HCC细胞， 在临床前模型中伤害正常细胞，在临床环境中成功的机会将增加。目标1： 在CRV + Ixz治疗的HCC中识别与凋亡性细胞死亡激活相关的介质，但在非CRV + Ixz治疗的HCC中不识别。 癌细胞目的2：研究口服生物可利用的CRV + Ixz组合在小鼠中的功效 HCC模型 在晚期HCC中，在发现新的化疗策略方面几乎没有进展。我们 建议通过口服联合治疗， 生物可利用的泛亲环素和UPS抑制剂将是选择性杀死HCC而不引起HCC的有用策略。 对正常组织产生过多的副作用。目前，CRV正在作为抗病毒和抗肝脏的药物进行研究。 我们是第一个提出将其用于HCC联合治疗的人。长期目标将是 使用CRV + Ixz治疗HCC患者，希望特异性地在HCC细胞中蛋白毒性应激细胞死亡 而不对正常组织造成毒性，将增加总存活率并改善生活质量。