Therapy for Liver Cancer by Targeting Energy Metabolism

通过靶向能量代谢治疗肝癌

• 批准号: 6869148
• 负责人: JEAN-FRANCOIS H GESCHWIND
• 金额: $ 28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869148
• 关键词: alkylating agents; antineoplastics; bioenergetics; cell growth regulation; cell line; drug design /synthesis /production; glycolysis; halocarbon compound; hepatocellular carcinoma; hexokinase; human tissue; intraarterial administration; laboratory rabbit; laboratory rat; liver neoplasms; metastasis; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; pyruvates

DESCRIPTION (provided by applicant): Liver cancer is one of the most highly lethal and incurable cancers in the world. In the United States, the incidence of liver cancer is growing rapidly (almost doubling every 3 years) due to the concomitant near-epidemic rise in hepatitis C. Our objective is to develop a new therapeutic strategy consisting of direct intraarterial delivery of potent inhibitors of energy metabolism to treat liver cancer. Most human malignant tumors including liver cancer consume glucose at high rates resulting in increased energy production essential for cell growth. This property is commonly used clinically in Positron Emission Tomography (PET) to detect cancers and assess their degree of malignancy. Work performed in our laboratory has determined the importance of glycolysis to generate energy for rapidly growing cancer cells. A major player in this process is Type II hexokinase, the initial enzyme of glucose metabolism located within the mitochondria, which is up-regulated in many cancer cells due to amplification of the Type II hexokinase gene, resulting in markedly increased activity. This increase in Type II hexokinase activity has recently been found in both primary and metastatic liver cancer as well as other human cancers, such as melanoma, breast, colon, and pancreas. Type II hexokinase therefore provides a new and ideal target for arresting glycolysis and thereby killing cancer cells. In earlier studies, we found that the alkylating agent, 3-bromopyruvate, induced rapid cell death (within 12 hours) of an entire rat hepatoma cell population in tissue culture. Here, 3-bromopyruvate, which had never been tested as an anti-cancer agent, acts as a specific inhibitor of tumor glycolysis both by blocking Type II hexokinase directly and inhibiting the mitochondrial ATP synthetic machinery. This dual action results in complete inhibition of the energy producing capabilities of cancer cells leading to their rapid death. In subsequent in-vivo studies, a single bolus injection of 3-bromopyruvate via the hepatic artery directly into rabbit implanted liver tumors caused over 90% tumor destruction without any toxicity to the liver or other organs. Prolonged intraarterial infusion of 3-bromopyruvate resulted in significantly prolonged survival and the cure of over 60% of the animals. At the time of sacrifice, 8 months after therapy, no viable tumor tissue was found at necropsy. The arterial route was selected to increase drug concentration within the tumor and maximize specificity. This preliminary work forms a firm foundation for the study proposed here, which is focused on developing a new approach in the treatment of liver cancer by direct intraarterial injection of agents that target energy metabolism. Specific aims are two-fold and will be to: 1) Characterize the expression of the high glycolytic/high Type II hexokinase phenotype in human liver tumors (freshly resected) thereby creating a library of hepatic tumors and establish the sensitivity of these tumors to 3-bromopyruvate; and 2) Study the efficacy of intraarterial therapy with 3-bromopyruvate on long-term survival and cure in the Vx-2 rabbit model of liver cancer. This translational study combining the use of radiological and basic science research tools is both necessary and fundamental to firmly lay the groundwork for clinical trials.

描述（由申请人提供）： 肝癌是世界上最致命和无法治愈的癌症之一。在美国，由于乙型肝炎的近乎流动性升高，肝癌的发生率正在迅速增长（几乎每3年增加一倍）。我们的目标是制定一种新的治疗策略，该策略由直接递送有效的能量代谢疗法的有效抑制剂组成，以治疗肝癌。包括肝癌在内的大多数人类恶性肿瘤以高速率消耗葡萄糖，从而增加了细胞生长必不可少的能量产生。该特性通常在正电子发射断层扫描（PET）中用于检测癌症并评估其恶性肿瘤程度。在我们的实验室中进行的工作确定了糖酵解为快速生长的癌细胞产生能量的重要性。此过程中的主要参与者是II型己糖酶，这是位于线粒体内的葡萄糖代谢的初始酶，由于II型己糖基因基因的扩增，许多癌细胞在许多癌细胞中被上调，导致活性显着增加。最近在原发性和转移性肝癌以及其他人类癌（例如黑色素瘤，乳腺癌，结肠癌和胰腺）中发现了II型己糖酶活性的增加。因此，II型己糖酶为阻止糖酵解并杀死癌细胞提供了一个新的理想目标。在较早的研究中，我们发现烷基化剂3-溴丙酮酸诱导整个大鼠肝癌细胞群体在组织培养中诱导快速细胞死亡（12小时内）。在这里，从未作为抗癌剂进行测试的3-溴丙酮酸，通过直接阻断II型己糖激酶并抑制线粒体ATP合成机制，作为肿瘤糖溶解的特定抑制剂。这种双重作用导致对癌细胞的能量产生能力的完全抑制，导致其快速死亡。在随后的体内研究中，通过肝动脉直接进入兔植入的肝肿瘤将3-溴丙酮酸注射到单一注射3-溴丙酮酸，造成超过90％的肿瘤破坏，而没有对肝脏或其他器官的毒性。长时间的3-溴丙酮酸内部输注导致生存率显着延长，并治愈超过60％的动物。在牺牲时，治疗8个月后，在尸检时未发现可行的肿瘤组织。选择动脉途径以增加肿瘤内的药物浓度并最大化特异性。这项初步工作构成了此处提出的研究的坚定基础，该研究的重点是通过直接靶向能量代谢的药物的直接注射药物来开发一种新方法来治疗肝癌。具体目的是两倍，将是：1）表征人肝肿瘤中高糖酵解/高型II型己糖酶表型的表达（新鲜切除），从而形成了肝肿瘤的库，并确定这些肿瘤对3-溴丙酮酸的敏感性； 2）研究肝癌VX-2兔模型中，使用3-溴丙酮酸对长期生存和治愈的疗法的功效。这项结合放射学和基础科学研究工具使用的翻译研究既是必要的，也是牢固为临床试验奠定基础的基础。