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Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets

Abstract

Altered cellular metabolism is a hallmark of gliomas. Propelled by a set of recent technological advances, new insights into the molecular mechanisms underlying glioma metabolism are rapidly emerging. In this Review, we focus on the dynamic nature of glioma metabolism and how it is shaped by the interaction between tumour genotype and brain microenvironment. Recent advances integrating metabolomics with genomics are discussed, yielding new insight into the mechanisms that drive glioma pathogenesis. Studies that shed light on interactions between the tumour microenvironment and tumour genotype are highlighted, providing important clues as to how gliomas respond to and adapt to their changing tissue and biochemical contexts. Finally, a road map for the discovery of potential new glioma drug targets is suggested, with the goal of translating these new insights about glioma metabolism into clinical benefits for patients.

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Fig. 1: Glioma nutrient uptake and utilization.
Fig. 2: RTK signalling regulates glioma metabolism.
Fig. 3: Glioma IDH mutations define metabolic dependencies.
Fig. 4: A roadmap for finding actionable metabolic dependencies in malignant gliomas.
Fig. 5: An expanded pharmacopoeia of metabolic drug targets in malignant glioma.

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References

  1. Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Weller, M. et al. Glioma. Nat. Rev. Dis. Prim. 1, 15017 (2015).

    Article  PubMed  Google Scholar 

  3. Cloughesy, T. F., Cavenee, W. K. & Mischel, P. S. Glioblastoma: from molecular pathology to targeted treatment. Annu. Rev. Pathol. 9, 1–25 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444–450 (2014). Brennan et al. (2013), Parsons et al. (2008), Suzuki et al. (2015), Wu et al. (2012) and Wu et al. (2014) describe the genomic landscape of gliomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  PubMed  Google Scholar 

  10. Vander Heiden, M. G. & DeBerardinis, R. J. Understanding the Intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  11. Venneti, S. & Thompson, C. B. Metabolic reprogramming in brain tumors. Annu. Rev. Pathol. 12, 515–545 (2017).

    Article  CAS  PubMed  Google Scholar 

  12. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu, J. & Thompson, C. B. Metabolic regulation of cell growth and proliferation. Nat. Rev. Mol. Cell Biol. 20, 436–450 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Belanger, M., Allaman, I. & Magistretti, P. J. Brain energy metabolism: focus on astrocyte–neuron metabolic cooperation. Cell Metab. 14, 724–738 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Bruce, K. D., Zsombok, A. & Eckel, R. H. Lipid processing in the brain: a key regulator of systemic metabolism. Front. Endocrinol. 8, 60 (2017).

    Article  Google Scholar 

  17. O’Brien, J. S. & Sampson, E. L. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J. Lipid Res. 6, 537–544 (1965).

    PubMed  Google Scholar 

  18. Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Zielke, H. R., Zielke, C. L. & Baab, P. J. Direct measurement of oxidative metabolism in the living brain by microdialysis: a review. J. Neurochem. 109, 24–29 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaur, B. et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol. 7, 134–153 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kayama, T., Yoshimoto, T., Fujimoto, S. & Sakurai, Y. Intratumoral oxygen pressure in malignant brain tumor. J. Neurosurg. 74, 55–59 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Kucharzewska, P., Christianson, H. C. & Belting, M. Global profiling of metabolic adaptation to hypoxic stress in human glioblastoma cells. PLOS ONE 10, e0116740 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019). This study demonstrates that synaptic integration may promote glioma progression.

    Article  CAS  PubMed  Google Scholar 

  25. Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 15, 827–837 (2012). This study is the first to demonstrate that GBM cells utilize mitochondrial glucose oxidation during aggressive tumour growth in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014). This study is the first to demonstrate that acetate is a bioenergetic substrate for GBM and brain metastases.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tanaka, K. et al. Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J. Clin. Invest. 125, 1591–1602 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tardito, S. et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat. Cell Biol. 17, 1556–1568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gu, Y. et al. mTORC2 regulates amino acid metabolism in cancer by phosphorylation of the cystine-glutamate antiporter xCT. Mol. Cell 67, 128–138.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cheng, T. et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA 108, 8674–8679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Oizel, K. et al. Efficient mitochondrial glutamine targeting prevails over glioblastoma metabolic plasticity. Clin. Cancer Res. 23, 6292–6304 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Venneti, S. et al. Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci. Transl. Med. 7, 274ra17 (2015). This article develops a glutamine-based, PET imaging strategy for gliomas.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Salamanca-Cardona, L. et al. In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in IDH1/2 mutant tumors. Cell Metab. 26, 830–841.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). This study is the first to demonstrate that D2HG is a product of IDH1 mutants in cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dietschy, J. M. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol. Chem. 390, 287–293 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dietschy, J. M. & Turley, S. D. Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12, 105–112 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Bjorkhem, I. & Meaney, S. Brain cholesterol: long secret life behind a barrier. Arterioscler. Thromb. Vasc. Biol. 24, 806–815 (2004).

    Article  PubMed  CAS  Google Scholar 

  44. Pfrieger, F. W. & Ungerer, N. Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Murakami, M. et al. Cholesterol uptake by human glioma cells via receptor-mediated endocytosis of low-density lipoprotein. J. Neurosurg. 73, 760–767 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Villa, G. R. et al. An LXR–cholesterol axis creates a metabolic co-dependency for brain cancers. Cancer Cell 30, 683–693 (2016). This study demonstrates that LXR-623, a clinically viable, highly brain-penetrant LXR agonist, selectively targets GBM cells in a cholesterol-dependent fashion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hamilton, J. A., Brunaldi, K., Bazinet, R. P. & Watkins, P. A. In Neural Metabolism In Vivo (eds. Choi, I.-Y. & Gruetter, R.) 793–817 (Springer US, 2012).

  48. Rohrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).

    Article  PubMed  CAS  Google Scholar 

  49. Guo, D. et al. EGFR signaling through an Akt–SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal. 2, ra82 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gimple, R. C. et al. Glioma stem cell specific super enhancer promotes polyunsaturated fatty acid synthesis to support EGFR signaling. Cancer Discov. 9, 1248–1267 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cancer Genome Atlas Research Network et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

    Article  CAS  Google Scholar 

  52. Riemenschneider, M. J. et al. Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 59, 6091–6096 (1999).

    CAS  PubMed  Google Scholar 

  53. Mai, W. X. et al. Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma. Nat. Med. 23, 1342–1351 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kruiswijk, F., Labuschagne, C. F. & Vousden, K. H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393–405 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Muller, P. A. & Vousden, K. H. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25, 304–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6021–6026 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Furnari, F. B., Cloughesy, T. F., Cavenee, W. K. & Mischel, P. S. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat. Rev. Cancer 15, 302–310 (2015). This review highlights the importance of amplification and mutation in the genes encoding RTKs, as well as the heterogeneity in GBM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nathanson, D. A. et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343, 72–76 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Verhaak, R. G. W., Bafna, V. & Mischel, P. S. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat. Rev. Cancer 19, 283–288 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. deCarvalho, A. C. et al. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat. Genet. 50, 708–717 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Masui, K., Cavenee, W. K. & Mischel, P. S. mTORC2 in the center of cancer metabolic reprogramming. Trends Endocrinol. Metab. 25, 364–373 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Agnihotri, S. & Zadeh, G. Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions. Neuro Oncol. 18, 160–172 (2016).

    Article  PubMed  Google Scholar 

  65. Babic, I. et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab. 17, 1000–1008 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Masui, K. et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab. 18, 726–739 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Griffiths, B. et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 1, 3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Porstmann, T. et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8, 224–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Guo, D. et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 1, 442–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bi, J. et al. Oncogene amplification in growth factor signaling pathways renders cancers dependent on membrane lipid remodeling. Cell Metab. 30, 525–538 e8 (2019). This article demonstrates an EGFR-driven metabolic dependency on membrane lipid remodelling in GBM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Martin, D. D., Robbins, M. E., Spector, A. A., Wen, B. C. & Hussey, D. H. The fatty acid composition of human gliomas differs from that found in nonmalignant brain tissue. Lipids 31, 1283–1288 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Masui, K. et al. Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc. Natl Acad. Sci. USA 112, 9406–9411 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Dang, C. V. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 3, a014217 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell Biol. 27, 7381–7393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kim, J. W. et al. Evaluation of MYC E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol. Cell Biol. 24, 5923–5936 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Osthus, R. C. et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Tateishi, K. et al. Myc-driven glycolysis is a therapeutic target in glioblastoma. Clin. Cancer Res. 22, 4452–4465 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mair, R. et al. Metabolic imaging detects low levels of glycolytic activity that vary with levels of c-Myc expression in patient-derived xenograft models of glioblastoma. Cancer Res. 78, 5408–5418 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Wang, X. et al. MYC-regulated mevalonate metabolism maintains brain tumor-initiating cells. Cancer Res. 77, 4947–4960 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bott, A. J. et al. Oncogenic Myc induces expression of glutamine synthetase through promoter demethylation. Cell Metab. 22, 1068–1077 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yang, C. et al. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 69, 7986–7993 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu, F. et al. EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol. Cell 60, 307–318 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Yang, W. et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150, 685–696 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yang, W. et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480, 118–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yang, W. et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat. Cell Biol. 14, 1295–1304 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kim, D. et al. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520, 363–367 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Waitkus, M. S., Diplas, B. H. & Yan, H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 18, 16–26 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Dang, L., Jin, S. & Su, S. M. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. L. M. G., Boulay K., Topisirovic, I., Huot, M. E. & Mallette, F. A. Oncogenic activities of IDH1/2 mutations: from epigenetics to cellular signaling. Trends Cell Biol. 27, 738–752 (2017).

    Article  CAS  Google Scholar 

  91. Cancer Genome Atlas Research Network et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

    Article  CAS  Google Scholar 

  92. Reitman, Z. J., Parsons, D. W. & Yan, H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell 17, 215–216 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ward, P. S. 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 17, 225–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Venneti, S. & Thompson, C. B. Metabolic modulation of epigenetics in gliomas. Brain Pathol. 23, 217–221 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. McBrayer, S. K. et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101–116.e25 (2018). This study demonstrates a metabolic dependency of IDH1 mutant glioma cells in redox homeostasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bi, J., Wu, S., Zhang, W. & Mischel, P. S. Targeting cancer’s metabolic co-dependencies: a landscape shaped by genotype and tissue context. Biochim. Biophys. Acta Rev. Cancer 1870, 76–87 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Carbonneau, M. et al. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat. Commun. 7, 12700 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Duncan, C. G. et al. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res. 22, 2339–2355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Fu, X. et al. 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab. 22, 508–515 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li, X. et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol. Cell 66, 684–697 e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cheng, C. et al. Glucose-mediated N-glycosylation of SCAP is essential for SREBP-1 activation and tumor growth. Cancer Cell 28, 569–581 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chhipa, R. R. et al. AMP kinase promotes glioblastoma bioenergetics and tumour growth. Nat. Cell Biol. 20, 823–835 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Padfield, E., Ellis, H. P. & Kurian, K. M. Current therapeutic advances targeting EGFR and EGFRvIII in glioblastoma. Front. Oncol. 5, 5 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Thiessen, B. et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother. Pharmacol. 65, 353–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Banks, W. A. From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat. Rev. Drug. Discov. 15, 275–292 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Beckner, M. E. et al. Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int. J. Cancer 126, 2282–2295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Duman, C. et al. Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metab. 30, 274–289 e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Chowdhry, S. et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 569, 570–575 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Phillips, R. E. et al. Target identification reveals lanosterol synthase as a vulnerability in glioma. Proc. Natl Acad. Sci. USA 116, 7957–7962 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Reitman, Z. J. et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc. Natl Acad. Sci. USA 108, 3270–3275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Waitkus, M. S., Diplas, B. H. & Yan, H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell 34, 186–195 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Waitkus, M. S. et al. Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1(R132H)-induced metabolic liabilities. Cancer Res. 78, 36–50 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Chen, R. et al. Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proc. Natl Acad. Sci. USA 111, 14217–14222 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shames, D. S. et al. Loss of NAPRT1 expression by tumor-specific promoter methylation provides a novel predictive biomarker for NAMPT inhibitors. Clin. Cancer Res. 19, 6912–6923 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Tateishi, K. et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28, 773–784 (2015). This study demonstrates a metabolic dependency of IDH1 mutant glioma cells in NAD metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tonjes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Mack, S. C., Hubert, C. G., Miller, T. E., Taylor, M. D. & Rich, J. N. An epigenetic gateway to brain tumor cell identity. Nat. Neurosci. 19, 10–19 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pfister, S. X. & Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug. Discov. 16, 241–263 (2017).

    Article  CAS  PubMed  Google Scholar 

  125. Cosset, E. et al. Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma. Cancer Cell 32, 856–868.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Atif, F., Yousuf, S., Espinosa-Garcia, C., Sergeeva, E. & Stein, D. G. Progesterone treatment attenuates glycolytic metabolism and induces senescence in glioblastoma. Sci. Rep. 9, 988 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Boado, R. J., Black, K. L. & Pardridge, W. M. Gene expression of GLUT3 and GLUT1 glucose transporters in human brain tumors. Brain Res. Mol. Brain Res. 27, 51–57 (1994).

    Article  CAS  PubMed  Google Scholar 

  128. Miranda-Goncalves, V. et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 15, 172–188 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Li, J. et al. Suppression of lactate dehydrogenase A compromises tumor progression by downregulation of the Warburg effect in glioblastoma. Neuroreport 27, 110–115 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sanzey, M. et al. Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. PLOS ONE 10, e0123544 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Ashton, T. M., McKenna, W. G., Kunz-Schughart, L. A. & Higgins, G. S. Oxidative phosphorylation as an emerging target in cancer therapy. Clin. Cancer Res. 24, 2482–2490 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Weinberg, S. E. & Chandel, N. S. Targeting mitochondria metabolism for cancer therapy. Nat. Chem. Biol. 11, 9–15 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Pelicano, H., Martin, D. S., Xu, R. H. & Huang, P. Glycolysis inhibition for anticancer treatment. Oncogene 25, 4633–4646 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Hay, N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat. Rev. Cancer 16, 635–649 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dunbar, E. M. et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest. New. Drugs 32, 452–464 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Sesen, J. et al. Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLOS ONE 10, e0123721 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02780024?cond=metformin%2C+glioma&draw=2&rank=3 (2016).

  138. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03243851?cond=metformin%2C+glioma&draw=2&rank=4 (2017).

  139. Shi, Y. et al. Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature 567, 341–346 (2019). This article, along with Molina et al. (2018) below, identifies ways to target GBM by inhibiting oxidative phosphorylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Molina, J. R. et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat. Med. 24, 1036–1046 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Polson, E. S. et al. KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. Sci. Transl. Med. 10, eaar2718 (2018).

    Article  PubMed  CAS  Google Scholar 

  142. Kaushik, A. K. & DeBerardinis, R. J. Applications of metabolomics to study cancer metabolism. Biochim. Biophys. Acta Rev. Cancer 1870, 2–14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim, M. M., Parolia, A., Dunphy, M. P. & Venneti, S. Non-invasive metabolic imaging of brain tumours in the era of precision medicine. Nat. Rev. Clin. Oncol. 13, 725–739 (2016). This review comprehensively describes a series of non-invasive metabolic-imaging approaches and opportunities for monitoring brain tumours in the clinic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. la Fougere, C., Suchorska, B., Bartenstein, P., Kreth, F. W. & Tonn, J. C. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro Oncol. 13, 806–819 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Choi, C. et al. 2-Hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 18, 624–629 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Andronesi, O. C. et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci. Transl Med. 4, 116ra4 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Andronesi, O. C. et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate. Nat. Commun. 9, 1474 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Choi, C. et al. Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma. J. Clin. Oncol. 34, 4030–4039 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Ludwig Institute for Cancer Research and by grants from the National Institute for Neurological Diseases and Stroke (NS73831), the Defeat GBM Program of the National Brain Tumour Society, and the Ben and Catherine Ivy Foundation, as well as by an award from the Sharpe/National Brain Tumour Society Research Program and a Compute for the Cure Award from the Nvidia Foundation (to P.S.M.).

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P.S.M., J.B., S.W. and S.C. researched data for the article, contributed to the discussion of content, wrote the article and reviewed or edited the manuscript before submission. W.Z. contributed to the discussion of content and the writing of the article. K.M. researched data for the article, contributed to the discussion of content and reviewed or edited the manuscript before submission.

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Correspondence to Paul S. Mischel.

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P.S.M. is a co-founder of Boundless Bio, Inc. He has equity and serves as a consultant for the company. P.S.M. also did a one-time consultation for Abide Therapeutics, Inc. The other authors declare no competing interests.

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Glossary

Gliomas

Tumours that arise within the brain and resemble the constituent glial cells. They are classified histologically as astrocytomas, oligodendrogliomas or ependymomas and are now also classified on the basis of molecular features.

Glioblastoma

(GBM). The most aggressive form of glioma, often referred to as grade IV astrocytoma.

Metabolic flux

The turnover rate of a metabolite, which is determined by the rates of the forward and reverse reactions in a metabolic pathway.

Acetate

A two-carbon molecule that can react with coenzyme A in the presence of ATP to generate acetyl-CoA.

Receptor tyrosine kinase

(RTK). A class of transmembrane cell surface receptors for ligands including growth factors, cytokines and hormones, to propagate kinase-cascading signalling.

MYC

Family of proto-oncogenes that encode transcription factors that regulate a wide range of biological functions, including cell proliferation and metabolism. In the human genome, it consists of three members: c-MYC (MYC), L-MYC (MYCL) and N-MYC (MYCN).

Phosphatidylcholine

A class of phospholipids with a choline head group; a major lipid component of cell membranes.

Metabolic dependencies

Reliance on a metabolite or metabolic pathway for survival.

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Bi, J., Chowdhry, S., Wu, S. et al. Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets. Nat Rev Cancer 20, 57–70 (2020). https://doi.org/10.1038/s41568-019-0226-5

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