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

手术切除或肝移植仍然是肝细胞癌患者唯一的治疗选择 癌症(HCC)。然而，只有不到20%的肝细胞癌患者适合切除。经动脉 栓塞术加或不加化疗(TA(C)E)是一种血管内局部栓塞术， 包括肝动脉栓塞术和动脉内注入化疗药物。Ta(C)E为 认为在其余80%的患者中治疗不能切除的肝细胞癌的护理标准。而TA(C)E 已经证实对生存有好处，局部复发很常见，长期存活率很低。此外，只有 经TA(C)E治疗后，44%的肝细胞癌在病理上显示广泛的坏死，表明有肿瘤细胞 形成适应性代谢应激反应(MSR)，使它们能够在TA(C)E诱导的营养下存活 和缺氧症。 在初步研究中，我们已经证明，肝癌细胞是预先编程的，能够在TA(C)E诱导下存活 自噬功能增强所致的缺血。此外，TA(C)E诱导的缺血可导致静止 在存活的肝癌细胞和对自噬的依赖中。因此，这些数据表明，TA(C)E提供了一个 限制代谢表型的独特机会，以便在肝细胞癌中产生这种有针对性的依赖性。 拟议的项目将建立在这一先前工作的基础上：1)研究以此为目标的新的TA(C)E范式 缺血诱导的对使用羟基氯喹(HCQ)的自噬的依赖2)是其疗效的特征 以及使用HCQ抑制自噬的演变以及抗肿瘤免疫的相关变化。至 实现这些目标，这份意见书提出了第一项人类早期前瞻性临床试验 评估动脉内(IA)HCQ联合TAE抑制自噬的安全性和有效性 栓塞术后每日口服HCQ维持6周的自噬抑制。随访肿瘤 栓塞后3-4周和5-6周的活检和血清采样将告知达标疗效 自噬抑制及其对肿瘤微环境和免疫反应的影响。 我们假设，在栓塞诱导的缺血中存活的肝细胞癌细胞的静止诱导呈现 它们依赖于自噬，自噬可以靶向增强TAE的细胞毒效应，并增强 抗肿瘤免疫反应。为了验证这一假设，拟议的项目将追求三个目标：(1) 建立自噬抑制剂HCQ联合TAE治疗慢性粒细胞白血病患者的临床安全性 中期肝细胞癌(1期)；(2)比较HCQ联合TAE与单纯TAE的短期疗效 中期肝细胞癌患者(2期)；和(3)确定局部和全身的差异 TAE后免疫调节作用与IA HCQ TAE的比较。拟议目标的实现是成立的 改变不能切除的肝细胞癌患者治疗模式的潜力。

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.