Therapy for Liver Cancer by Targeting Energy Metabolism

Summary

Principal Investigator: Jean Francois Geschwind
Abstract: 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.
Funding Period: 2005-04-01 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. pmc Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study
    Mustafa Vali
    Russell H Morgan Department of Radiology and Radiological Sciences, Division of Vascular and Interventional Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
    J Pharmacol Exp Ther 327:32-7. 2008
  2. pmc Quantitative and volumetric European Association for the Study of the Liver and Response Evaluation Criteria in Solid Tumors measurements: feasibility of a semiautomated software method to assess tumor response after transcatheter arterial chemoembolizati
    MingDe Lin
    Clinical Informatics, Interventional, and Translational Solutions CIITS, Philips Research North America, Briarcliff Manor, New York, USA
    J Vasc Interv Radiol 23:1629-37. 2012
  3. pmc Spontaneous tumor regression in a syngeneic rat model of liver cancer: implications for survival studies
    Manon Buijs
    Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Blalock 545, Baltimore, MD 21287, USA
    J Vasc Interv Radiol 23:1685-91. 2012
  4. ncbi The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma
    Ihab R Kamel
    Russell H Morgan Department of Radiology and Radiological Sciences, Division of Vascular and Interventional Radiology, Baltimore, MD 21287, USA
    J Vasc Interv Radiol 17:505-12. 2006
  5. ncbi Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra-arterial treatment with 3-bromopyruvate and chemoembolization
    Josephina A Vossen
    Division of Vascular and Interventional Radiology, Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 545, Baltimore, MD 21287, USA
    Clin Exp Metastasis 25:811-7. 2008
  6. pmc Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death
    Shanmugasundaram Ganapathy-Kanniappan
    Russell H Morgan Department of Radiology and Radiological Sciences, Baltimore, MD 21287, USA
    Anticancer Res 29:4909-18. 2009

Detail Information

Publications6

  1. pmc Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: a biodistribution and survival study
    Mustafa Vali
    Russell H Morgan Department of Radiology and Radiological Sciences, Division of Vascular and Interventional Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA
    J Pharmacol Exp Ther 327:32-7. 2008
    ..The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit...
  2. pmc Quantitative and volumetric European Association for the Study of the Liver and Response Evaluation Criteria in Solid Tumors measurements: feasibility of a semiautomated software method to assess tumor response after transcatheter arterial chemoembolizati
    MingDe Lin
    Clinical Informatics, Interventional, and Translational Solutions CIITS, Philips Research North America, Briarcliff Manor, New York, USA
    J Vasc Interv Radiol 23:1629-37. 2012
    ..To show that hepatic tumor volume and enhancement pattern measurements can be obtained in a time-efficient and reproducible manner on a voxel-by-voxel basis to provide a true three-dimensional (3D) volumetric assessment...
  3. pmc Spontaneous tumor regression in a syngeneic rat model of liver cancer: implications for survival studies
    Manon Buijs
    Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Blalock 545, Baltimore, MD 21287, USA
    J Vasc Interv Radiol 23:1685-91. 2012
    ..These results were compared with tumor growth after implantation with McA-RH7777 cells...
  4. ncbi The role of functional MR imaging in the assessment of tumor response after chemoembolization in patients with hepatocellular carcinoma
    Ihab R Kamel
    Russell H Morgan Department of Radiology and Radiological Sciences, Division of Vascular and Interventional Radiology, Baltimore, MD 21287, USA
    J Vasc Interv Radiol 17:505-12. 2006
    ..To assess treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with use of diffusion and dynamic contrast medium-enhanced magnetic resonance (MR) imaging...
  5. ncbi Development of a new orthotopic animal model of metastatic liver cancer in the rabbit VX2 model: effect on metastases after partial hepatectomy, intra-arterial treatment with 3-bromopyruvate and chemoembolization
    Josephina A Vossen
    Division of Vascular and Interventional Radiology, Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 545, Baltimore, MD 21287, USA
    Clin Exp Metastasis 25:811-7. 2008
    ..In order to achieve our objective, we tested the feasibility of both resection, intra-arterial therapy with 3-BrPA and TACE of VX2 liver cancer in New Zealand White rabbits...
  6. pmc Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pyruvylated during 3-bromopyruvate mediated cancer cell death
    Shanmugasundaram Ganapathy-Kanniappan
    Russell H Morgan Department of Radiology and Radiological Sciences, Baltimore, MD 21287, USA
    Anticancer Res 29:4909-18. 2009
    ..Yet, there is a lack of experimental documentation on the direct interaction of 3BrPA with any of the suggested targets during its anticancer effect...