A New Strategy to Increase Proteotoxic Cell Death in Hepatocellular Carcinoma

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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.