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    Awarded Grants
    Stop Breast Cancer with 3-BrPA, a Recently Discovered Anti-Metabolite with Strong Inhibiting Activity Against Primary and Metastatic Liver Cancer.

    Scientific Abstract:
    Stop Breast Cancer with 3-BrPA, a Recently Discovered Anti-metabolite with Strong Inhibitory Activity against Primary and Metastatic Liver Cancer. Background: This application focuses on the chemically simple compound 3-bromopyruvic acid (3-BrPA), an analog of the natural metabolite pyruvate. We have recently discovered that 3-BrPA is a potent inhibitor of hepatocellular carcinoma cells in tissue culture, of liver implanted tumors in a rabbit model, and of metastatic lung nodules derived from the liver implanted tumors. Regarding its mechanism, we have shown that 3-BrPA selectively accesses the energy machinery of tumor cells, most likely via a specific or elevated transporter in these cells. Once inside, 3-BrPA becomes a total energy blocker, inhibiting ATP production derived from both glycolysis and mitochondria, thus reducing cell ATP levels so dramatically as to induce cell death. A key target is Type II hexokinase, a mitochondrial bound enzyme found at high levels in many rapidly growing tumors that exhibit a high glycolytic phenotype, i.e., a high capacity to take up glucose, convert it to lactic acid, and then transport this end product out of the cell. Perhaps equally important, we have shown that 3-BrPA exhibits no obvious toxic side effects based on pathological examination of normal tissues or careful observance of the general health and well-being of animals (rabbits and rats). Finally, and very pertinent to this new application, we have now discovered that this remarkable agent is also a potent inhibitor of all breast cancer cell lines tested to date in tissue culture. Objective/Hypothesis: Our objective is to test the efficacy of 3-BrPA as an inhibitor of primary and metastatic mammary carcinomas in animal models. We will commence with the established “MNU” (N-methyl-N-nitrosourea) model in the female rat because it shows similarities to human breast cancers, both in its hormone dependency and its propensity to metastasize to the lungs and liver. Our hypothesis is that 3-BrPA will be a potent energy blocker of both MNU-induced primary breast cancers and of their distantly established metastatic progeny, and that the animals harboring these tumors will have no or very minimal side effects as assessed by both pathological examination of normal tissues, and careful monitoring of their general health and well-being. Specific Aims: The First Specific Aim is to compare the relative effectiveness of 3-BrPA as an anti-breast cancer agent in MNU-induced primary cancers when injected systemically, i.e., via a tail vein, and when injected directly at or near the site of the tumor. The Second Specific Aim will be to determine to what extent 3-BrPA is effective against both advanced stage MNU-induced mammary tumors and their metastatic products that have appeared in the lungs and liver. Study Design: To accomplish our specific aims we will commence by inducing mammary carcinoma in female rats with MNU following established procedures. This procedure is nearly 100% effective in inducing mammary tumors. In the initial experiments, we will use 60 female rats and divide them into 6 different groups of 10 each. One group (D) will receive a direct injection of 3-BrPA at the tumor site; a second group (S) will receive a systemic injection of 3-BrPA via the tail vein; and a third group (DS) will receive both a direct injection of 3-BrPA at the tumor site and via the tail vein. The other three groups designated C-D, C-S, and C-DS will be controls (C) for the D, S, and DS groups, respectively. They will receive no 3-BrPA, only saline, via the same procedure as the experimental group. Experimental data will be collected and compared among different groups, e.g., tumor size as a function of time, pathology of the tumors and normal tissues, cell ATP levels, and animal health and behavior. Experiments will be repeated to arrive at optimal therapeutic doses and for statistical purposes. Specific Aim 2 focused on advanced stage tumors and metastasis there from will be carried out in a similar fashion but working with more animals as all MNU tumors do not result in metastasis. Potential Outcomes and Benefits: This research may lead to a new, effective, minimally toxic drug, mechanistically different from all others, and which can stop early, advanced, and metastatic breast cancers and improve the quality of life for millions who suffer from this horrible disease.

    Lay Abstract:
    Stop Breast Cancer with 3-BrPA, a Recently Discovered Anti-metabolite with Strong Inhibitory Activity against Primary and Metastatic Liver Cancer. Background: This project will focus on the newly discovered anti-breast cancer activity of the small, chemically simple compound 3-bromopyruvic acid (3-BrPA). This agent is an analog of the natural metabolite pyruvate, a breakdown product of sugar metabolism in humans and animals. Significantly, we have shown recently that 3-BrPA is exceptionally effective as an inhibitor of liver cancer cells growing in tissue culture, of liver implanted tumors in rabbits, and of lung tumors resulting from metastasis. Remarkable aspects of 3-BrPA are its killing efficacy (80-100%), the low doses necessary to achieve this killing, and its apparent non-toxicity. Normal tissues within animals remain healthy while tumor tissues are attacked. The mechanism by which 3-BrPA destroys tumors is distinct from currently used high profile cancer drugs, as it targets the cell’s energy producing machinery, both glycolysis (glucose breakdown) and mitochondria. Most recently, we have shown that 3-BrPA is also a highly effective inhibitor of human breast cancer cells (slow and rapidly growing) in tissue culture, thus leading to this proposal. Objective/Hypothesis: Our objective is to test the efficacy of 3-BrPA as an inhibitor of primary and metastatic breast cancer in animal models. We will commence with the established “MNU” (N-methyl-N-nitrosourea) model in the female rat because it shows similarities to human breast cancers, both in its hormone dependency and its propensity under defined conditions to metastasize to the lungs and liver. Our hypothesis is that 3-BrPA will be a potent energy blocker of both MNU-induced primary breast cancers and of their distantly established metastatic progeny, and that the animals harboring these tumors will have no or very minimal side effects as assessed by both pathological examination of normal tissues, and careful monitoring of their general health and well-being. Specific Aims: The First Specific Aim is to compare the relative effectiveness of 3-BrPA as an anti-breast cancer agent in MNU-induced primary cancers when injected systemically, i.e., via a tail vein, and when injected directly at or near the site of the tumor. The Second Specific Aim will be to determine to what extent 3-BrPA is effective against both advanced stage MNU-induced breast cancers and their metastatic products that have appeared in the lungs and liver. Study Design: To accomplish our specific aims we will commence by inducing breast cancers in female rats with MNU following an established procedure. This procedure is nearly 100% effective in inducing breast cancers. In the initial experiments, we will use 60 female rats and divide them into 6 different groups of 10 each. One group (D) will receive a direct injection of 3-BrPA at the tumor site; a second group (S) will receive a systemic injection of 3-BrPA via the tail vein; and a third group (DS) will receive both a direct injection of 3-BrPA at the tumor site and via the tail vein. The other three groups designated C-D, C-S, and C-DS will be controls (C) for the D, S, and DS groups, respectively. They will receive no 3-BrPA, only saline, via the same procedure as the experimental group. Experimental data will be collected and compared among different groups, e.g., tumor size as a function of time, pathology of the tumors and normal tissues, cell ATP levels, and animal health and behavior. Experiments will be repeated to arrive at optimal therapeutic doses and for statistical purposes. Specific Aim 2 focused on advanced stage tumors and metastasis there from will be carried out in a similar fashion but working with more animals as all MNU tumors do not result in metastasis. Potential Outcomes and Benefits: The proposed research has the potential of leading to a new, effective, minimally toxic drug, mechanistically different from all others, and which can stop early, advanced, and metastatic breast cancers and improve the quality of life for millions who suffer from this horrible disease both in the U. S. and throughout the world.