Targeting Ischemia-Induced Autophagy Dependence in hepatocellular Carcinoma through Image-guided Locoregional Therapy

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Surgical resection or liver transplantation remain the only curative options for patients with hepatocellular carcinoma (HCC). However, fewer than 20% of patients with HCC are candidates for resection. Transarterial embolization with or without chemotherapy (TA(C)E) is an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent. TA(C)E is considered the standard of care for treating unresectable HCC in the remaining 80% of patients. While TA(C)E has a proven survival benefit, local recurrence is common, and long-term survival rates are poor. Moreover, only 44% of treated HCCs demonstrate extensive necrosis on pathology following TA(C)E, indicating tumor cells develop an adaptive metabolic stress response (MSR) enabling their survival under TA(C)E-induced nutrient and oxygen deprivation. In preliminary studies, we have demonstrated that HCC cells are pre-programmed to survive TA(C)E-induced ischemia through enhanced function of autophagy. Moreover, TA(C)E-induced ischemia results in quiescence in surviving HCC cells and a dependence on autophagy. As such, these data demonstrate that TA(C)E offers a unique opportunity to constrain metabolic phenotypes in order to generate this targetable dependency in HCC. The proposed project will build on this prior work to: 1) study a novel TA(C)E paradigm which targets this ischemia-induced dependency on autophagy using hydroxychloroquine (HCQ) and 2) characterizes the efficacy and evolution of autophagy inhibition using HCQ as well as associated alterations in anti-tumor immunity. To achieve these goals, this submission proposes a first in human, early phase prospective clinical trial to assess the safety and efficacy of autophagy inhibition using intra-arterial (IA) HCQ with TAE followed by maintenance of autophagy inhibition with daily oral HCQ for 6 weeks following embolization. Follow-up tumor biopsies and serum sampling 3-4 and 5-6 weeks after embolization will inform on the on-target efficacy of autophagy inhibition and its effect on the tumor microenvironment and immune response. We hypothesize that the induction of quiescence in HCC cells surviving embolization-induced ischemia renders them dependent on autophagy which can be targeted to potentiate the cytotoxic effects of TAE as well enhance the anti-tumor immune response. To test this hypothesis the proposed project will pursue three aims: (1) to establish the clinical safety of the combination of the autophagy inhibitor HCQ with TAE to treat patients with intermediate stage HCC (phase 1); (2) to compare the short-term efficacy of HCQ with TAE versus TAE alone in patients with intermediate stage HCC (phase 2); and (3) to characterize differences in local and systemic immune modulation following TAE as compared to IA HCQ TAE. The achievement of the proposed aims holds the potential to transform treatment paradigms for patients with unresectable HCC, an incurable disease.