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）： 肝癌是世界上最高致命性和不可治愈的癌症之一。在美国，肝癌的发病率正在迅速增长（几乎每3年翻一番），这是由于丙型肝炎的流行性增加。我们的目标是开发一种新的治疗策略，包括直接动脉内递送有效的能量代谢抑制剂来治疗肝癌。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，导致细胞生长所必需的能量产生增加。该特性通常用于正电子发射断层扫描（PET）的临床检测癌症和评估其恶性程度。在我们实验室进行的工作已经确定了糖酵解为快速生长的癌细胞产生能量的重要性。该过程中的主要参与者是II型己糖激酶，其是位于线粒体内的葡萄糖代谢的初始酶，由于II型己糖激酶基因的扩增，其在许多癌细胞中上调，导致活性显著增加。最近在原发性和转移性肝癌以及其他人类癌症如黑色素瘤、乳腺癌、结肠癌和胰腺癌中发现了II型己糖激酶活性的这种增加。因此，II型己糖激酶为阻止糖酵解从而杀死癌细胞提供了一个新的理想靶点。在早期的研究中，我们发现，烷化剂，3-溴丙酮酸，诱导快速细胞死亡（在12小时内）的整个大鼠肝癌细胞群在组织培养。在这里，从未被测试为抗癌剂的3-溴丙酮酸通过直接阻断II型己糖激酶和抑制线粒体ATP合成机制来作为肿瘤糖酵解的特异性抑制剂。这种双重作用导致完全抑制癌细胞的能量产生能力，导致其快速死亡。在随后的体内研究中，3-溴丙酮酸通过肝动脉直接单次推注到兔植入的肝肿瘤中引起超过90%的肿瘤破坏，而对肝脏或其他器官没有任何毒性。延长动脉内输注3-溴丙酮酸导致显着延长生存和治愈超过60%的动物。在处死时，治疗后8个月，尸检时未发现存活的肿瘤组织。选择动脉途径以增加肿瘤内的药物浓度并最大化特异性。这项初步工作为本文提出的研究奠定了坚实的基础，该研究的重点是通过直接动脉内注射靶向能量代谢的药物来开发治疗肝癌的新方法。具体目标是双重的，并且将是：1）表征人肝肿瘤（新鲜切除的）中高糖酵解/高II型己糖激酶表型的表达，从而创建肝肿瘤文库并建立这些肿瘤对3-溴丙酮酸的敏感性;和2）研究用3-溴丙酮酸进行动脉内治疗对Vx-2兔肝癌模型中的长期存活和治愈的功效。这种结合使用放射学和基础科学研究工具的转化研究是必要的，也是为临床试验奠定基础的基础。