Targeting Ischemia-Induced Dependencies on the Metabolic Stress Response in Hepatocellular Carcinoma Through Image-Guided, Locoregional Therapy

通过图像引导的局部治疗，针对肝细胞癌中缺血引起的代谢应激反应依赖性

• 批准号: 10400072
• 负责人: Terence P Gade
• 金额: $ 41.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400072
• 关键词: Achievement; Address; Adjuvant Therapy; Arteries; Autophagocytosis; Biology; Blood Vessels; Cancer Etiology; Catheters; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Cessation of life; Chemoembolization; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Data; Dependence; Disease; Enzymes; Excision; Extensive Necrosis; Feeds; Fructose-1,6-Bisphosphatase; Genes; Growth; Hepatic artery; Histopathology; Hypoxia Inducible Factor; Image; In Vitro; Individual; Intra-Arterial Infusions; Ischemia; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Metabolic; Metabolic Activation; Metabolic stress; Molecular; Molecular Target; Mutation; Necrosis; Nutrient; Operative Surgical Procedures; Oxygen; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Primary carcinoma of the liver cells; Proteins; Rattus; Recurrence; Research; Role; Survival Rate; Techniques; Testing; Therapeutic; Therapeutic Embolization; Translating; Transplantation; United States; Unresectable; Validation; Vascular blood supply; Work; advanced disease; biological adaptation to stress; cancer cell; cancer therapy; chemotherapeutic agent; clinical translation; clinically relevant; common treatment; cytotoxic; deprivation; follow-up; genome editing; image guided; improved; in vivo; inhibitor; liver cancer model; liver transplantation; metabolic phenotype; neoplastic cell; new therapeutic target; novel; nutrient deprivation; optimal treatments; particle; patient population; randomized trial; response; standard of care; therapeutic target; therapy development; translational approach; tumor; tumor microenvironment; 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 chemoembolization (TACE) is an endovascular locoregional embolotherapy that involves hepatic artery embolization with intra-arterial infusion of a chemotherapeutic agent and is considered the standard of care for treating unresectable HCC in the remaining 80% of patients with this disease. While TACE 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 TACE, indicating that tumor cells develop an adaptive metabolic stress response (MSR) enabling their survival under TACE-induced nutrient and oxygen deprivation. In preliminary studies, we have demonstrated that HCC cells may be pre-programmed to survive TACE-induced ischemia through enhanced function of the MSR, including autophagy and hypoxia-inducible factors (HIFs). Moreover, TACE-induced ischemia results in quiescence in surviving HCC cells and further activation of the MSR. These data demonstrate that TACE offers a unique opportunity to constrain metabolic phenotypes in order to generate targetable dependencies in HCC. The proposed project will build on this prior work to: 1) further characterize the role of targetable MSR pathways in enabling HCC cell survival under TACE-like ischemia and 2) validate a synergistic therapeutic strategy that targets this MSR dependence in order to define a novel, and more effective, approach to TACE. Gene editing will be used to examine the roles of fructose bisphosphatase 1 and urea cycle enzymes in influencing the basal activity of HIFs and autophagy, respectively in HCC cells. The dependence of HCC cell survival on each of the MSR pathways individually and in combination will be determined through gene editing and pharmacologic inhibition. Our recently developed, unique autochthonous rat model of HCC and TACE will be utilized to assess the TACE-induced essentiality of each MSR pathway in vivo using pharmacological inhibitors of the MSR. We hypothesize that the induction of quiescence in HCC cells surviving TACE-induced ischemia renders them dependent on MSR pathways which can be targeted to potentiate the cytotoxic effects of TACE. To test this hypothesis the proposed project will pursue three aims: (1) to define genetic alterations that contribute to molecular and cellular stress response pathway activation in HCC in vitro and in vivo; (2) to functionally demonstrate the dependence of HCC cells surviving severe ischemia on induction of the MSR in vitro; and (3) to determine the efficacy of potentiating TACE-induced ischemia by individual and simultaneous pharmacologic targeting of the MSR in vivo. Importantly, the proposed project emphasizes a translational approach, so that the achievement of these aims will directly inform and influence the treatment of 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 化疗栓塞（TACE）是一种涉及肝动脉的血管内局部栓塞疗法 通过动脉内输注化疗剂进行栓塞，被认为是治疗的标准 治疗剩余 80% 的不可切除的 HCC 患者。虽然 TACE 的生存率已得到证实 但局部复发常见，长期生存率较差。此外，只有 44% 的接受治疗的 HCC TACE 后病理学表现出广泛的坏死，表明肿瘤细胞形成了适应性 代谢应激反应（MSR）使它们能够在 TACE 诱导的营养和氧气剥夺下生存。 在初步研究中，我们已经证明 HCC 细胞可能经过预先编程以在 TACE 诱导的情况下存活 通过增强 MSR 功能（包括自噬和缺氧诱导因子 (HIF)）来缓解缺血。 此外，TACE 诱导的缺血导致存活的 HCC 细胞静止并进一步激活 MSR。这些数据表明，TACE 提供了一个独特的机会来限制代谢表型，以便 在 HCC 中生成可定位的依赖关系。拟议的项目将建立在先前工作的基础上：1）进一步 表征可靶向 MSR 通路在 TACE 样缺血下使 HCC 细胞存活的作用，以及 2) 验证针对这种 MSR 依赖性的协同治疗策略，以定义一种新颖的、和 更有效的 TACE 方法。基因编辑将用于检查果糖双磷酸酶 1 的作用 和尿素循环酶分别影响 HCC 细胞中 HIF 和自噬的基础活性。这 HCC 细胞存活对每条 MSR 途径（单独或组合）的依赖性 通过基因编辑和药物抑制来确定。我们最近开发的、独特的本土 HCC 和 TACE 大鼠模型将用于评估 TACE 诱导的每个 MSR 途径的重要性 体内使用MSR的药理学抑制剂。 我们假设在 TACE 诱导的缺血中幸存的 HCC 细胞中诱导静止使它们 依赖于 MSR 途径，可以针对该途径增强 TACE 的细胞毒性作用。为了测试这个 假设拟议的项目将追求三个目标：（1）定义有助于 HCC 体外和体内分子和细胞应激反应途径的激活； (2) 功能上 证明 HCC 细胞在严重缺血中存活对体外 MSR 诱导的依赖性；和（3） 确定通过单独和同时的药理学增强 TACE 诱导的缺血的功效 体内MSR的靶向。重要的是，拟议的项目强调转化方法，以便 这些目标的实现将直接指导和影响不可切除的 HCC 患者的治疗， 不治之症。