title: Clinical development of cancer therapeutics that target metabolism.
abstract: Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of adenosine triphosphate and the anabolic precursors needed for survival, growth and motility. The recent observations that mutant oncogenic proteins and the loss of tumor suppressors activate key metabolic enzymes suggest that selective inhibition of these enzymes may yield effective cancer therapeutics with acceptable toxicities. In support of this concept, pre-clinical studies of small molecule antagonists of several metabolic enzymes in tumor-bearing mice have demonstrated reasonable therapeutic indices. We will review the rationale for targeting metabolic enzymes as a strategy to treat cancer and will detail the results of several recent clinical trials of metabolic inhibitors in advanced cancer patients.
authors.affiliation: From the Department of Biochemistry and Molecular Genetics, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40292 brian.clem@louisville.edu jason.chesney@louisville.edu.
authors.forename: B F
authors.initials: BF
authors.lastname: Clem
authors.affiliation: Department of Medicine, Washington University, 660 South Euclid Ave, St. Louis, MO 63110.
authors.forename: J
authors.initials: J
authors.lastname: O'Neal
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville and Molecular Targets Program, James Graham Brown Cancer Center, 505 South Hancock Street, Louisville, KY 40202, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Klarer
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville and Molecular Targets Program, James Graham Brown Cancer Center, 505 South Hancock Street, Louisville, KY 40202, USA.
authors.forename: S
authors.initials: S
authors.lastname: Telang
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, University of Louisville and Molecular Targets Program, James Graham Brown Cancer Center, 505 South Hancock Street, Louisville, KY 40202, USA brian.clem@louisville.edu jason.chesney@louisville.edu.
authors.forename: J
authors.initials: J
authors.lastname: Chesney
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015195:Drug Design; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy / Q000639:trends; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor