Ow the growth of xenografted tumors. The development of more specific inhibitors of GDH may allow for more efficacious MedChemExpress Vorapaxar targeting of glutamine flux into the TCA cycle. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Alterations to the TCA cycle in cancer metabolism In addition to utilizing aerobic glycolysis and glutamine metabolism for proliferation and survival, it has become clear in recent years that some cancer cells extensively also alter normal TCA cycle metabolism towards these ends. Typically thought of as acting in support of oxidative mitochondrial metabolism, the TCA cycle can also be adapted to produce cell building blocks for proliferation. As one example, citrate produced from acetyl CoA in the TCA cycle can be exported from the mitochondria and converted into raw material for the synthesis of fatty acids that are needed for cell proliferation. The TCA cycle flow can be reversed in reductive carboxylation so that -ketoglutarate is converted to isocitrate then citrate for lipid synthesis. Also, interestingly, mutations that contribute to oncogenesis and the maintenance and progression of established tumors have been identified in several TCA enzymes. To date, several mutations have been identified in TCA cycle enzymes, including succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase. SDH and FH have come to be thought of as tumor suppressors, as mutations in either enzyme has been shown to cause sarcomas, renal cell carcinoma and other rare types of cancer. IDH mutations are found in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19849834 gliomas and acute myeloid leukemias, and evidence implicates them in other cancer settings. These mutations result in a gain of function, allowing IDH to begin producing a new “oncometabolite” called -2-hydroxyglutarate. 2HG itself has been termed an oncometabolite and has the capacity to transform immortalized cells in vitro, through mechanisms that remain somewhat unclear. Numerous studies provide evidence that increased 2HG in cells harboring IDH mutations can inhibit demethylases, leading to hypermethylated DNA and retention of a stem cell-like phenotype. Targeting the TCA cycle in cancer metabolism Small molecule based targeting of abnormalities in the TCA cycle has become one of the greatest successes to date in therapeutically attacking cancer metabolism. While success targeting mutant FH and SDH with small molecule inhibitors has been limited because these are loss of function mutations, novel compounds that inhibit the gain-of-function activity of Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 7 mutant IDH have recently been shown to have success in Vorapaxar preclinical and clinical settings. In preclinical studies, small molecule inhibition of mutant IDH has been shown to dramatically reduce the production of 2HG and cause cancerous cells to differentiate towards a more normal phenotype. Early phase clinical trials have begun with a small molecule inhibitor of mutant IDH2, AG-221. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Challenges of targeting cancer metabolism While there are numerous potential therapeutic targets in cancer metabolism, there are profound challenges associated with utilizing metabolic inhibition as a clinical strategy. First among these challenges is the fact that it is difficult to achieve a therapeutic window in cancer metabolism, as many normal cells, especially rapidly proliferating cells of the immune system,.Ow the growth of xenografted tumors. The development of more specific inhibitors of GDH may allow for more efficacious targeting of glutamine flux into the TCA cycle. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Alterations to the TCA cycle in cancer metabolism In addition to utilizing aerobic glycolysis and glutamine metabolism for proliferation and survival, it has become clear in recent years that some cancer cells extensively also alter normal TCA cycle metabolism towards these ends. Typically thought of as acting in support of oxidative mitochondrial metabolism, the TCA cycle can also be adapted to produce cell building blocks for proliferation. As one example, citrate produced from acetyl CoA in the TCA cycle can be exported from the mitochondria and converted into raw material for the synthesis of fatty acids that are needed for cell proliferation. The TCA cycle flow can be reversed in reductive carboxylation so that -ketoglutarate is converted to isocitrate then citrate for lipid synthesis. Also, interestingly, mutations that contribute to oncogenesis and the maintenance and progression of established tumors have been identified in several TCA enzymes. To date, several mutations have been identified in TCA cycle enzymes, including succinate dehydrogenase, fumarate hydratase and isocitrate dehydrogenase. SDH and FH have come to be thought of as tumor suppressors, as mutations in either enzyme has been shown to cause sarcomas, renal cell carcinoma and other rare types of cancer. IDH mutations are found in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19849834 gliomas and acute myeloid leukemias, and evidence implicates them in other cancer settings. These mutations result in a gain of function, allowing IDH to begin producing a new “oncometabolite” called -2-hydroxyglutarate. 2HG itself has been termed an oncometabolite and has the capacity to transform immortalized cells in vitro, through mechanisms that remain somewhat unclear. Numerous studies provide evidence that increased 2HG in cells harboring IDH mutations can inhibit demethylases, leading to hypermethylated DNA and retention of a stem cell-like phenotype. Targeting the TCA cycle in cancer metabolism Small molecule based targeting of abnormalities in the TCA cycle has become one of the greatest successes to date in therapeutically attacking cancer metabolism. While success targeting mutant FH and SDH with small molecule inhibitors has been limited because these are loss of function mutations, novel compounds that inhibit the gain-of-function activity of Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 7 mutant IDH have recently been shown to have success in preclinical and clinical settings. In preclinical studies, small molecule inhibition of mutant IDH has been shown to dramatically reduce the production of 2HG and cause cancerous cells to differentiate towards a more normal phenotype. Early phase clinical trials have begun with a small molecule inhibitor of mutant IDH2, AG-221. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Challenges of targeting cancer metabolism While there are numerous potential therapeutic targets in cancer metabolism, there are profound challenges associated with utilizing metabolic inhibition as a clinical strategy. First among these challenges is the fact that it is difficult to achieve a therapeutic window in cancer metabolism, as many normal cells, especially rapidly proliferating cells of the immune system,.

Ow the growth of xenografted tumors. The development of more specific

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