A New Strategy to Increase Proteotoxic Cell Death in Hepatocellular Carcinoma

泛素蛋白酶体系统的抑制物(UPS，降解未折叠蛋白质的主要途径) 增加蛋白毒性应激，对多发性骨髓瘤有临床成功，但对实体癌，如 肝细胞癌(HCC)。进一步加强固体蛋白毒性应激的当前临床策略 通过联合泛组蛋白脱乙酰酶(HDAC)UPS抑制剂治疗肿瘤取得了一些成功，但也带来了 对正常组织有很高的毒性。我们提出了一种替代策略来增强肝细胞癌的蛋白毒性应激，但 通过将新的泛亲环素抑制剂CRV431(CRV)与A 第二代UPS抑制剂Ixazomib(Ixz)。由于亲环素在蛋白质折叠中很重要，因此结合一个 泛亲环素抑制剂，如CRV，增加错误折叠的蛋白质并用UPS阻止其降解 像Ixz这样的抑制剂会放大蛋白毒性应激，并迫使细胞凋亡。 我们的初步数据支持使用CRV Ixz作为一种新的治疗肝癌的策略 对非癌细胞产生毒性。我们建议维持较高水平的支持生存反应 介体XBP1s(未折叠蛋白反应)和低亲环素表达/活性触发肝细胞癌细胞死亡 细胞。值得注意的是，与肝癌细胞相比，CRV Ixz在非癌症细胞中没有毒性，而目前的蛋白质毒性 应激组合Panobinostat(临床相关的PAN-HDAC抑制剂)Ixz在非癌症患者中同样具有毒性 和肝癌细胞。 这一建议的假设是CRV Ixz维持高XBP_1和低亲环素 表达/活性压倒促生存途径，迫使肝癌细胞走向凋亡细胞 死亡而不损害正常细胞。其基本原理是，如果这种新的组合在没有 在临床前模型中损害正常细胞，在临床环境中成功的机会将增加。目标1： 确定CRV Ixz治疗的肝癌中与凋亡细胞死亡激活有关的介质，而不是在非CRV Ixz治疗的肝癌中 癌细胞。目的2：研究口服生物利用型CRV Ixz制剂对小鼠的疗效 肝细胞癌模型。 在晚期肝癌中，在发现新的化疗策略方面进展甚微。我们 建议联合口服靶向必要的蛋白毒性应激反应生存通路 生物可利用的泛环亲和素和UPS抑制剂将是一种有用的策略，可以选择性地杀死肝癌而不会导致 对正常组织有过多的副作用。目前，CRV正在被研究为一种抗病毒和抗肝脏的药物。 我们首次提出将其用于肝细胞癌的联合治疗。长期目标将是 使用CRV Ixz治疗肝癌患者，希望蛋白质毒性应激细胞在肝癌细胞中特异性死亡 不会对正常组织造成毒性，将增加总体存活率和改善生活质量。

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.