Therapy for Liver Cancer by Targeting Energy Metabolism

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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.