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

通过图像引导局部治疗靶向肝细胞癌中缺血诱导的自噬依赖性

• 批准号: 10585078
• 负责人: Terence P Gade
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585078
• 关键词: Achievement; Ammonia; Arterial Embolization; Arteries; Autophagocytosis; Biology; Biopsy; Blood Vessels; Cancer Etiology; Catheters; Cell Survival; Cell physiology; Cells; Cessation of life; Chemoembolization; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dependence; Disease; Dose; Eating; Evolution; Excision; Extensive Necrosis; Feeds; General Population; Goals; Granzyme; Growth; Hepatic artery; Hepatocyte; Hepatotoxicity; Histologic; Histopathology; Hydroxychloroquine; Image; Immune; Immune response; In Vitro; Interruption; Intra-Arterial Infusions; Ischemia; Liver; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Metabolic; Metabolic Activation; Metabolic stress; Molecular; Necrosis; Nutrient; Nutritional Requirements; Operative Surgical Procedures; Oral; Oxygen; Pathology; Patients; Pattern; Phase; Phenotype; Portal vein structure; Primary carcinoma of the liver cells; Procedures; Progression-Free Survivals; Randomized; Recurrence; Safety; Sampling; Serum; Survival Rate; T cell clonality; Testing; Therapeutic; Therapeutic Embolization; Transplantation; Tumor Immunity; Unresectable; Vascular blood supply; Veterans; Work; anti-tumor immune response; biological adaptation to stress; cancer therapy; cell killing; chemotherapeutic agent; chemotherapy; cytotoxic; cytotoxicity; deprivation; epigenetic silencing; first-in-human; follow-up; image guided; image guided therapy; immunoregulation; improved; improved outcome; in vivo; inhibition of autophagy; inhibitor; liver transplantation; metabolic phenotype; minimally invasive; neoplastic cell; new therapeutic target; novel; novel strategies; nutrient deprivation; patient population; perforin; prospective; response; safety assessment; standard of care; treatment response; tumor; tumor microenvironment; tumor-immune system interactions; urea cycle

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.

手术切除或肝移植仍然是肝细胞性肝癌患者唯一的治疗选择 癌（HCC）。然而，只有不到 20% 的 HCC 患者适合切除。经动脉 联合或不联合化疗的栓塞术 (TA(C)E) 是一种血管内局部栓塞疗法， 涉及肝动脉栓塞和动脉内输注化疗剂。 TA(C)E 是 考虑治疗其余 80% 患者的不可切除 HCC 的护理标准。而TA(C)E 已证实具有生存益处，但局部复发常见，长期生存率较低。而且，仅 44% 的治疗 HCC 在 TA(C)E 后病理学上表现出广泛的坏死，表明肿瘤细胞 发展适应性代谢应激反应 (MSR)，使其能够在 TA(C)E 诱导的营养条件下生存 和缺氧。 在初步研究中，我们已经证明 HCC 细胞经过预先编程，可以在 TA(C)E 诱导的情况下存活 通过增强自噬功能来缓解缺血。此外，TA(C)E 诱导的缺血导致静止 存活的 HCC 细胞和对自噬的依赖。因此，这些数据表明 TA(C)E 提供了 这是限制代谢表型的独特机会，以便在 HCC 中产生这种可靶向的依赖性。 拟议的项目将建立在先前工作的基础上：1）研究一种针对此目标的新颖的 TA(C)E 范式 缺血诱导的对使用羟氯喹 (HCQ) 的自噬的依赖性和 2) 表征了功效 使用 HCQ 抑制自噬的演变以及抗肿瘤免疫的相关改变。到 为了实现这些目标，本申请提出了第一个人体早期前瞻性临床试验 使用动脉内 (IA) HCQ 结合 TAE 评估自噬抑制的安全性和有效性，然后 栓塞后每日口服 HCQ 维持自噬抑制 6 周。肿瘤随访 栓塞后 3-4 周和 5-6 周进行活检和血清取样将了解栓塞治疗的目标疗效 自噬抑制及其对肿瘤微环境和免疫反应的影响。 我们假设，在栓塞引起的缺血中幸存的 HCC 细胞中诱导静止使得 它们依赖于自噬，可以靶向增强 TAE 的细胞毒性作用并增强 抗肿瘤免疫反应。为了检验这一假设，拟议项目将追求三个目标：（1） 建立自噬抑制剂 HCQ 与 TAE 联合治疗患有以下疾病的患者的临床安全性 中期 HCC（第一阶段）； (2) 比较 HCQ 联合 TAE 与单独 TAE 的短期疗效 中期 HCC 患者（第 2 期）； (3) 表征局部和系统的差异 与 IA HCQ TAE 相比，TAE 后的免疫调节。实现拟议目标 改变不可切除的 HCC（一种不治之症）患者的治疗模式的潜力。