Skip to main content
SpringerLink
Log in

Metabolic Enzymes in Sarcomagenesis: Progress Toward Biology and Therapy

  • Leading Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Cellular metabolism reprogramming is an emerging hallmark of cancer, which provides tumor cells with not only necessary energy but also crucial materials to support growth. Exploiting the unique features of cancer metabolism is promising in cancer therapies. The growing interest in this field has led to numerous inhibitors being developed against key molecules in metabolic pathways, though most of them are still in preclinical development. Potential targeted cancer cell metabolic pathways under investigation include glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, pentose phosphate pathway (PPP), lipid synthesis, amino acid and nucleotide metabolism. Sarcoma is a type of cancer that arises from transformed cells of mesenchymal origin, in contrast to carcinoma which originates from epithelial cells. Compared with carcinoma, progress towards harnessing the therapeutic potential of targeting sarcoma cell metabolism has been relatively slow. Recently however, with the discovery of cancer-specific mutations in metabolic enzymes such as isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH) in certain sarcoma types, cancer cellular metabolism has been considered more as a source of new targets for treating sarcoma. In this article, we review metabolic enzymes currently tested for cancer therapies and describe the therapeutic potential of targeting IDH mutations and SDH deficiency in sarcomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  3. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82.

    Article  CAS  PubMed  Google Scholar 

  5. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703–7.

    Article  CAS  PubMed  Google Scholar 

  7. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  8. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23(5):537–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov. 2013;12(11):829–46.

    Article  CAS  PubMed  Google Scholar 

  10. Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14(1):11–31.

    Article  CAS  PubMed  Google Scholar 

  11. Gallamini A, Zwarthoed C, Borra A. Positron emission tomography (PET) in oncology. Cancers. 2014;6(4):1821–89.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mankoff DA, Eary JF, Link JM, Muzi M, Rajendran JG, Spence AM, et al. Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond. Clin Cancer Res. 2007;13(12):3460–9.

    Article  CAS  PubMed  Google Scholar 

  13. Dwarakanath BS, Singh D, Banerji AK, Sarin R, Venkataramana NK, Jalali R, et al. Clinical studies for improving radiotherapy with 2-deoxy-d-glucose: present status and future prospects. J Cancer Res Ther. 2009;5(Suppl 1):S21–6.

    Article  CAS  PubMed  Google Scholar 

  14. Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, et al. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol. 2003;21(18):3462–8.

    Article  CAS  PubMed  Google Scholar 

  15. Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene. 2008;27(34):4636–43.

    Article  CAS  PubMed  Google Scholar 

  16. Jae HJ, Chung JW, Park HS, Lee MJ, Lee KC, Kim HC, et al. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model. Korean J Radiol. 2009;10(6):596–603.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther. 2013;12(8):1461–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452(7184):230-U74.

    Google Scholar 

  19. Dang CV. PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect. Sci Signal. 2009;2(97):pe75. doi:10.1126/scisignal.297pe75.

    Article  PubMed  CAS  Google Scholar 

  20. Gupta V, Bamezai RNK. Human pyruvate kinase M2: A multifunctional protein. Protein Sci. 2010;19(11):2031–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Michels J, Obrist F, Castedo M, Vitale I, Kroemer G. PARP and other prospective targets for poisoning cancer cell metabolism. Biochem Pharmacol. 2014;92(1):164–71.

    Article  CAS  PubMed  Google Scholar 

  22. Khan JA, Forouhar F, Tao X, Tong L. Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Tar. 2007;11(5):695–705.

    Article  CAS  Google Scholar 

  23. Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest New Drug. 2008;26(1):45–51.

    Article  CAS  Google Scholar 

  24. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. P Natl Acad Sci USA. 2010;107(5):2037–42.

    Article  CAS  Google Scholar 

  25. Mutz CN, Schwentner R, Aryee DNT, Bouchard EDJ, Mejia EM, Hatch GM, et al. EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells. Oncotarget. 2017;8(15):24679–93.

    PubMed  PubMed Central  Google Scholar 

  26. Hirschhaeuser F, Sattler UGA, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71(22):6921–5.

    Article  CAS  PubMed  Google Scholar 

  27. Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol. 2004;14(3):267–74.

    Article  PubMed  Google Scholar 

  28. Finbow ME, Harrison MA. The vacuolar H+-ATPase: a universal proton pump of eukaryotes. Biochem J. 1997;324:697–712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sennoune SR, Martinez-Zaguilan R. Vacuolar H+-ATPase signaling pathway in cancer. Curr Protein Pept Sc. 2012;13(2):152–63.

    Article  CAS  Google Scholar 

  30. Michel V, Licon-Munoz Y, Trujillo K, Bisoffi M, Parra KJ. Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. Int J Cancer. 2013;132(2):E1–10.

    Article  CAS  PubMed  Google Scholar 

  31. Avnet S, Di Pompo G, Lemma S, Salerno M, Perut F, Bonuccelli G, et al. V-ATPase is a candidate therapeutic target for Ewing sarcoma. Bba Mol Basis Dis. 2013;1832(8):1105–16.

    Article  CAS  Google Scholar 

  32. Perut F, Avnet S, Fotia C, Baglio SR, Salerno M, Hosogi S, et al. V-ATPase as an effective therapeutic target for sarcomas. Exp Cell Res. 2014;320(1):21–32.

    Article  CAS  PubMed  Google Scholar 

  33. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, et al. Metabolic Modulation of Glioblastoma with Dichloroacetate. Sci Transl Med. 2010;2(31). doi:10.1126/scitranslmed.3000677.

    Article  CAS  PubMed  Google Scholar 

  34. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008;99(7):989–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Papandreou I, Goliasova T, Denko NC. Anticancer drugs that target metabolism: is dichloroacetate the new paradigm? Int J Cancer. 2011;128(5):1001–8.

    Article  CAS  PubMed  Google Scholar 

  36. Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Power surge: Supporting cells “fuel” cancer cell mitochondria. Cell Metab. 2012;15(1):4–5.

    Article  CAS  PubMed  Google Scholar 

  37. Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov. 2010;9(6):447–64.

    Article  CAS  PubMed  Google Scholar 

  38. Barletta JA, Hornick JL. Succinate dehydrogenase-deficient tumors: diagnostic advances and clinical implications. Adv Anat Pathol. 2012;19(4):193–203.

    Article  CAS  PubMed  Google Scholar 

  39. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11–7.

    Article  CAS  PubMed  Google Scholar 

  40. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.

    Article  CAS  PubMed  Google Scholar 

  41. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Abbas S, Lugthart S, Kavelaars FG, Schelen A, Koenders JE, Zeilemaker A, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6.

    Article  CAS  PubMed  Google Scholar 

  43. Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS, et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem. 2007;282(5):3293–301.

    Article  CAS  PubMed  Google Scholar 

  44. Ponnaluri VK, Maciejewski JP, Mukherji M. A mechanistic overview of TET-mediated 5-methylcytosine oxidation. Biochem Biophys Res Commun. 2013;436(2):115–20.

    Article  CAS  PubMed  Google Scholar 

  45. Gottlieb E, Tomlinson IPM. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005;5(11):857–66.

    Article  CAS  PubMed  Google Scholar 

  46. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73(1):95–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, Lehtonen R, Pukkala E, Arola J, et al. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer. 2006;119(2):283–7.

    Article  CAS  PubMed  Google Scholar 

  48. Bo S, Ciccone G, Rosato R, Villois P, Appendino G, Ghigo E, et al. Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients. Diabetes Obes Metab. 2012;14(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  49. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Soga T. Cancer metabolism: key players in metabolic reprogramming. Cancer Sci. 2013;104(3):275–81.

    Article  CAS  PubMed  Google Scholar 

  51. Bauer DE, Hatzivassiliou G, Zhao FP, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005;24(41):6314–22.

    Article  CAS  PubMed  Google Scholar 

  52. Hatzivassiliou G, Zhao FP, Bauer DE, Andreadis C, Shaw AN, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8(4):311–21.

    Article  CAS  PubMed  Google Scholar 

  53. Anastasiou D, Cantley LC. Breathless cancer cells get fat on glutamine. Cell Res. 2012;22(3):443–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011;481(7381):380–4.

    PubMed  PubMed Central  Google Scholar 

  55. Filipp FV, Scott DA, Ronai ZA, Osterman AL, Smith JW. Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigm Cell Melanoma R. 2012;25(3):375–83.

    Article  CAS  Google Scholar 

  56. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313–24.

    Article  CAS  PubMed  Google Scholar 

  57. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70(22):8981–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15(1):110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890–901.

    Article  CAS  PubMed  Google Scholar 

  60. Pieter A, van den Heuvel J, Jing JP, Wooster RF, Bachman KE. Analysis of glutamine dependency in non-small cell lung cancer GLS1 splice variant GAC is essential for cancer cell growth. Cancer Biol Ther. 2012;13(12):1185–94.

    Article  CAS  Google Scholar 

  61. Gameiro PA, Yang JJ, Metelo AM, Perez-Carro R, Baker R, Wang ZW, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013;17(3):372–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Riganti C, Gazzano E, Polimeni M, Aldieri E, Ghigo D. The pentose phosphate pathway: an antioxidant defense and a crossroad in tumor cell fate. Free Radic Bio Med. 2012;53(3):421–36.

    Article  CAS  Google Scholar 

  63. Phan LM, Yeung SC, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014;11(1):1–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Foldi M, Stickeler E, Bau L, Kretz O, Watermann D, Gitsch G, et al. Transketolase protein TKTL1 overexpression: a potential biomarker and therapeutic target in breast cancer. Oncol Rep. 2007;17(4):841–5.

    PubMed  Google Scholar 

  65. Vizan P, Alcarraz-Vizan G, Diaz-Moralli S, Solovjeva ON, Frederiks WM, Cascante M. Modulation of pentose phosphate pathway during cell cycle progression in human colon adenocarcinoma cell line HT29. Int J Cancer. 2009;124(12):2789–96.

    Article  CAS  PubMed  Google Scholar 

  66. Xu XJ, Zur Hausen A, Coy JF, Lochelt M. Transketolase-like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells. Int J Cancer. 2009;124(6):1330–7.

    Article  CAS  PubMed  Google Scholar 

  67. Yuan W, Wu S, Guo J, Chen Z, Ge J, Yang P, et al. Silencing of TKTL1 by siRNA inhibits proliferation of human gastric cancer cells in vitro and in vivo. Cancer Biol Ther. 2010;9(9):710–6.

    Article  CAS  PubMed  Google Scholar 

  68. Chajes V, Cambot M, Moreau K, Lenoir GM, Joulin V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res. 2006;66(10):5287–94.

    Article  CAS  PubMed  Google Scholar 

  69. Beckers A, Organe S, Tinunermans L, Scheys K, Peeters A, Brusselmans K, et al. Chemical inhibition of Acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 2007;67(17):8180–7.

    Article  CAS  PubMed  Google Scholar 

  70. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010;6(4):551–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Giro A, Blancafort A, Oliveras G, Perez-Bueno F, Dorca J, Vinas G, et al. Fatty acid synthase inhibition as a potential therapeutic target in triple-negative breast cancer. Eur J Cancer. 2013;49:S180-S.

    Google Scholar 

  72. Seguin F, Carvalho MA, Bastos DC, Agostini M, Zecchin KG, Alvarez-Flores MP, et al. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br J Cancer. 2012;107(6):977–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Uddin S, Hussain AR, Ahmed M, Abubaker J, Al-Sanea N, AbdulJabbar A, et al. High prevalence of fatty acid synthase expression in colorectal cancers in Middle Eastern patients and its potential role as a therapeutic target. Am J Gastroenterol. 2009;104(7):1790–801.

    Article  CAS  PubMed  Google Scholar 

  74. Kubatka P, Kruzliak P, Rotrekl V, Jelinkova S, Mladosievicova B. Statins in oncological research: from experimental studies to clinical practice. Crit Rev Oncol Hemat. 2014;92(3):296–311.

    Article  Google Scholar 

  75. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. New Engl J Med. 2012;367(19):1792–802.

    Article  CAS  PubMed  Google Scholar 

  76. Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, et al. A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene. 2011;30(30):3370–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Glunde K, Bhujwalla ZM, Ronen SM. Choline metabolism in malignant transformation. Nat Rev Cancer. 2011;11(12):835–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chabner BA, Roberts TG. Timeline—chemotherapy and the war on cancer. Nat Rev Cancer. 2005;5(1):65–72.

    Article  CAS  PubMed  Google Scholar 

  79. Visentin M, Zhao RB, Goldman ID. The antifolates. Hematol Oncol Clin N. 2012;26(3):629–48.

    Article  Google Scholar 

  80. Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A. Structure of human dCK suggests strategies to improve anticancer and antiviral therapy. Nat Struct Biol. 2003;10(7):513–9.

    Article  CAS  PubMed  Google Scholar 

  81. Braas D, Ahler E, Tam B, Nathanson D, Riedinger M, Benz MR, et al. Metabolomics strategy reveals subpopulation of liposarcomas sensitive to gemcitabine treatment. Cancer Discov. 2012;2(12):1109–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lukey MJ, Katt WP, Cerione RA. Targeting amino acid metabolism for cancer therapy. Drug Discov Today. 2016. doi:10.1016/j.drudis.2016.12.003.

    PubMed  Google Scholar 

  83. Qiu F, Huang J, Sui M. Targeting arginine metabolism pathway to treat arginine-dependent cancers. Cancer Lett. 2015;364(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  84. Kremer JC, Prudner BC, Lange SE, Bean GR, Schultze MB, Brashears CB, et al. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Rep. 2017;18(4):991–1004.

    Article  CAS  PubMed  Google Scholar 

  85. Katz JB, Muller AJ, Prendergast GC. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008;222:206–21.

    Article  CAS  PubMed  Google Scholar 

  86. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80.

    Article  CAS  PubMed  Google Scholar 

  87. Vacchelli E, Aranda F, Eggermont A, Sautes-Fridman C, Tartour E, Kennedy EP, et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology. 2014;3(10):e957994.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Okamoto A, Nikaido T, Ochiai K, Takakura S, Saito M, Aoki Y, et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res. 2005;11(16):6030–9.

    Article  CAS  PubMed  Google Scholar 

  89. Urakawa H, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, Ishiguro N. Prognostic value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin Exp Metastasis. 2009;26(8):1005–12.

    Article  CAS  PubMed  Google Scholar 

  90. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17(9):1094–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhai L, Spranger S, Binder DC, Gritsina G, Lauing KL, Giles FJ, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res. 2015;21(24):5427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004;279(32):33946–57.

    Article  CAS  PubMed  Google Scholar 

  93. Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 2016;18(1):16–26.

    Article  PubMed  Google Scholar 

  94. Haselbeck RJ, McAlister-Henn L. Function and expression of yeast mitochondrial NAD- and NADP-specific isocitrate dehydrogenases. J Biol Chem. 1993;268(16):12116–22.

    CAS  PubMed  Google Scholar 

  95. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer I. 2010;102(13):932–41.

    Article  CAS  Google Scholar 

  96. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730–41.

    Article  CAS  PubMed  Google Scholar 

  98. Yen KE, Schenkein DP. Cancer-associated isocitrate dehydrogenase mutations. Oncol. 2012;17(1):5–8.

    Article  CAS  Google Scholar 

  99. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang Y, Paz Mejia A, Temple HT, Trent J, Rosenberg AE. Squamous cell carcinoma arising in dedifferentiated chondrosarcoma proved by isocitrate dehydrogenase mutation analysis. Hum Pathol. 2014;45(7):1541–5.

    Article  CAS  PubMed  Google Scholar 

  105. Tinoco G, Wilky BA, Paz-Mejia A, Rosenberg A, Trent JC. The biology and management of cartilaginous tumors: a role for targeting isocitrate dehydrogenase. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Meet. 2015. doi:10.14694/EdBook_AM.2015.35.e648.

    Google Scholar 

  106. Borger DR, Tanabe KK, Fan KC, Lopez HU, Fantin VR, Straley KS, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncol. 2012;17(1):72–9.

    Article  CAS  Google Scholar 

  107. Wang P, Dong Q, Zhang C, Kuan PF, Liu Y, Jeck WR, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene. 2013;32(25):3091–100.

    Article  CAS  PubMed  Google Scholar 

  108. Lopez GY, Reitman ZJ, Solomon D, Waldman T, Bigner DD, McLendon RE, et al. IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain. Biochem Biophys Res Commun. 2010;398(3):585–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shibata T, Kokubu A, Miyamoto M, Sasajima Y, Yamazaki N. Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation. Am J Pathol. 2011;178(3):1395–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tang JY, Chang CC, Lin PC, Chang JG. Isocitrate dehydrogenase mutation hot spots in acute lymphoblastic leukemia and oral cancer. Kaohsiung J Med Sci. 2012;28(3):138–44.

    Article  CAS  PubMed  Google Scholar 

  111. Sequist LV, Heist RS, Shaw AT, Fidias P, Rosovsky R, Temel JS, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Murugan AK, Bojdani E, Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem Biophys Res Commun. 2010;393(3):555–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fathi AT, Sadrzadeh H, Comander AH, Higgins MJ, Bardia A, Perry A, et al. Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate. Oncol. 2014;19(6):602–7.

    Article  CAS  Google Scholar 

  114. Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Seo SI, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer. 2009;125(2):353–5.

    Article  CAS  PubMed  Google Scholar 

  115. Ghiam AF, Cairns RA, Thoms J, Dal Pra A, Ahmed O, Meng A, et al. IDH mutation status in prostate cancer. Oncogene. 2012;31(33):3826.

    Article  CAS  PubMed  Google Scholar 

  116. Gaal J, Burnichon N, Korpershoek E, Roncelin I, Bertherat J, Plouin PF, et al. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2010;95(3):1274–8.

    Article  CAS  PubMed  Google Scholar 

  117. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502(7472):472–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Bio. 2013;14(6):341–56.

    Article  CAS  Google Scholar 

  120. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine. Oncotarget. 2013;4(10):1729–36.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340(6132):622–6.

    Article  CAS  PubMed  Google Scholar 

  126. Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013;340(6132):626–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015;125(2):296–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;529(7584):110–4.

    Article  CAS  PubMed  Google Scholar 

  129. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339(6127):1621–5.

    Article  CAS  PubMed  Google Scholar 

  132. Losman JA, Kaelin WG. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013;27(8):836–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cleven AHG, Suijker J, Agrogiannis G, Briaire-de Bruijn IH, Frizzell N, Hoekstra AS, et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin Sarcoma Res. 2017;7:8. doi:10.1186/s13569-017-0074-6.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Suijker J, Baelde HJ, Roelofs H, Cleton-Jansen AM, Bovee JVMG. The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or-2 blocks osteoblast differentiation in vitro and in vivo. Oncotarget. 2015;6(17):14832–42.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hansen E, Quivoron C, Straley K, Lemieux RM, Popovici-Muller J, Sadrzadeh H, et al. AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient Samples Treated Ex Vivo. Blood. 2014;124(21):3734.

  136. Quivoron C, David M, Straley K, Travins J, Kim H, Chen Y, et al. AG-221, an Oral, Selective, First-in-Class, Potent IDH2-R140Q Mutant Inhibitor, Induces Differentiation in a Xenotransplant Model. Blood. 2014;124(21):3735.

  137. Li L, Paz AC, Wilky BA, Johnson B, Galoian K, Rosenberg A, et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS One. 2015;10(9):e0133813.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia. 2017. doi:10.1038/leu.2017.46.

    Google Scholar 

  139. Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17(8):610–20.

    Article  CAS  PubMed  Google Scholar 

  140. Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. P Natl Acad Sci USA. 2011;108(1):314–8.

    Article  CAS  Google Scholar 

  141. Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer I. 2008;100(17):1260–2.

    Article  CAS  Google Scholar 

  142. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs)—a review. Int J Biochem Cell B. 2014;53:514–9.

    Article  CAS  Google Scholar 

  143. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865–78.

    CAS  PubMed  Google Scholar 

  144. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21(23):4342–9.

    Article  CAS  PubMed  Google Scholar 

  145. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.

    Article  CAS  PubMed  Google Scholar 

  146. Wang YM, Gu ML, Ji F. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol. 2015;21(8):2303–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Weldon CB, Madenci AL, Boikos SA, Janeway KA, George S, von Mehren M, et al. Surgical management of wild-type gastrointestinal stromal tumors: a report from the national institutes of health pediatric and wildtype GIST clinic. J Clin Oncol. 2016;35(5):523–8.

  148. Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011;35(11):1712–21.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85.

    Article  CAS  PubMed  Google Scholar 

  150. Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004;10(10):3282–90.

    Article  CAS  PubMed  Google Scholar 

  151. Chou A, Chen J, Clarkson A, Samra JS, Clifton-Bligh RJ, Hugh TJ, et al. Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression. Modern Pathol. 2012;25(9):1307–13.

    Article  CAS  Google Scholar 

  152. Nannini M, Biasco G, Astolfi A, Pantaleo MA. An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet. 2013;50(10):653–61.

    Article  CAS  PubMed  Google Scholar 

  153. Pantaleo MA, Astolfi A, Di Battista M, Heinrich MC, Paterini P, Scotlandi K, et al. Insulin-like growth factor 1 receptor expression in wild-type GISTs: a potential novel therapeutic target. Int J Cancer. 2009;125(12):2991–4.

    Article  CAS  PubMed  Google Scholar 

  154. Corless CL, Beadling C, Justusson E, Heinrich MC. Evaluation of the presence of IGF1R overexpression in wild-type and kinase mutant GI stromal tumors. J Clin Oncol. 2009;27(15):10506.

    Google Scholar 

  155. Songdej N, von Mehren M. GIST treatment options after tyrosine kinase inhibitors. Curr Treat Options Oncol. 2014;15(3):493–506.

    Article  PubMed  Google Scholar 

  156. Pollak M. The insulin receptor/insulin-like growth factor receptor family as a therapeutic target in oncology. Clin Cancer Res. 2012;18(1):40–50.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge partial support and assistance from the Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA

    Luyuan Li, Josiane E. Eid, Ana C. Paz & Jonathan C. Trent

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Luyuan Li, Josiane E. Eid, Ana C. Paz & Jonathan C. Trent

  3. Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    Luyuan Li & Jonathan C. Trent

Authors
  1. Luyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josiane E. Eid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana C. Paz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan C. Trent
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan C. Trent.

Ethics declarations

Funding

No funding was received for the preparation of this review.

Conflicts of interest

Luyuan Li, Josiane E. Eid, Ana C. Paz and Jonathan C. Trent declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Eid, J.E., Paz, A.C. et al. Metabolic Enzymes in Sarcomagenesis: Progress Toward Biology and Therapy. BioDrugs 31, 379–392 (2017). https://doi.org/10.1007/s40259-017-0237-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-017-0237-2

Search

Navigation