title: Targeted cancer therapeutics: biosynthetic and energetic pathways characterized by metabolomics and the interplay with key cancer regulatory factors.
abstract: Reprogramming of energy metabolism has recently been added to the list of hallmarks that define cancer. Cellular metabolism plays a central role in cancer initiation and progression to metastatic disease. Genotypic and phenotypic metabolic alterations are seen throughout tumourigenesis, allowing cancer cells to sustain increased rates of proliferation. Furthermore, this shift fuels necessary substrates for nucleotide, protein, and lipid synthesis to support cell growth. Beyond the 'Warburg effect', the widely observed increase in the glycolytic processing of glucose in cancer cells, numerous other metabolic changes have been characterized in cancer. Metabolomics provides a valuable platform for the investigation of the metabolic perturbations that occur in different disease states using a systems biology approach to determine metabolic profiles of biological samples. As cell metabolism is a complex network of interdependent pathways, local alterations will have an impact on overall tumor metabolism. In this review, we will highlight particular pathways, including glycolysis, nucleotide biosynthesis, lipid metabolism, and bioenergetics with an eye towards selected metabolic targets that may provide a novel approach to therapeutic development. Specific regulatory factors, including Myc, p53, HIF-1 and mTOR are briefly highlighted, as well as the key signaling pathways that can affect cellular metabolism. To demonstrate the powerful utility of high-throughput metabolite profiling techniques, we present a practical example of the metabolomic profiling of metastatic cells derived from a lung cancer metastasis model.
authors.forename: Ngoc-Ha T
authors.initials: NH
authors.lastname: Dang
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Singla
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mackay
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jirik
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Smilow Center for Translational Research, 3400 Civic Center Blvd, Bldg 421, Room 10-113, Philadelphia, Pennsylvania, USA 19104. aalim@upenn.edu.
authors.forename: Aalim M
authors.initials: AM
authors.lastname: Weljie
mesh_terms: D015687:Cell Hypoxia; D004734:Energy Metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D055432:Metabolomics; D008928:Mitochondria / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009711:Nucleotides / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009711:Nucleotides; D019869:Phosphatidylinositol 3-Kinases