Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B.
Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science
324, 1029–1033 (2009).
Luo, J., Solimini, N. L. & Elledge, S. J.
Principles of cancer therapy: oncogene and non-oncogene addiction. Cell
136, 823–837 (2009).
Tennant, D. A., Duran, R. V. & Gottlieb, E.
Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer
10, 267–277 (2010).
Deberardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B.
The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell. Metab.
7, 11–20 (2008).
Cairns, R. A., Harris, I. S. & Mak, T. W.
Regulation of cancer cell metabolism. Nature Rev. Cancer
11, 85–95 (2011).
Groves, A. M., Win, T., Haim, S. B. & Ell, P. J.
Non-[18F]FDG PET in clinical oncology. Lancet Oncol.
8, 822–830 (2007).
Dimitrakopoulou-Strauss, A. & Strauss, L. G.
PET imaging of prostate cancer with 11C-acetate. J. Nucl. Med.
44, 556–558 (2003).
Ben-Haim, S. & Ell, P.
18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med.
50, 88–99 (2009).
Tessem, M. B.
et al. Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR-MAS spectroscopy of biopsy tissues. Magn. Reson. Med.
60, 510–516 (2008).
Kaelin, W. G., Jr & Ratcliffe, P. J.
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell
30, 393–402 (2008).
Semenza, G. L.
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene
29, 625–634 (2010).
Zoncu, R., Efeyan, A. & Sabatini, D. M.
mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol.
12, 21–35 (2011).
Vander Heiden, M. G.
et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science
329, 1492–1499 (2010).
Calle, E. E. & Kaaks, R.
Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer
4, 579–591 (2004).
Insulin and insulin-like growth factor signalling in neoplasia. Nature Rev. Cancer
8, 915–928 (2008).
Wellen, K. E. & Thompson, C. B.
Cellular metabolic stress: considering how cells respond to nutrient excess. Mol. Cell
40, 323–332 (2010).
Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J.
Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med.
348, 1625–1638 (2003).
Jee, S. H.
et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA
293, 194–202 (2005).
Weiser, M. A.
et al. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer
100, 1179–1185 (2004).
Meyerhardt, J. A.
et al. Impact of diabetes mellitus on outcomes in patients with colon cancer. J. Clin. Oncol.
21, 433–440 (2003).
et al. Pretreatment prognostic factors for survival in small-cell lung cancer: a new prognostic index and validation of three known prognostic indices on 341 patients. Ann. Oncol.
8, 547–553 (1997).
Eschwege, E. & Balkau, B.
Hyperglycaemia: link to excess mortality. Int. J. Clin. Pract. Suppl.
123, S3–S6 (2001).
Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D.
Metformin and reduced risk of cancer in diabetic patients. BMJ
330, 1304–1305 (2005). This paper was the first to report a decreased risk of death from cancer for patients with diabetes who were taking metformin, which sparked a series of papers examining the possible benefits of metformin in cancer therapy.
Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A.
Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care
29, 254–258 (2006).
El-Mir, M. Y.
et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem.
275, 223–228 (2000).
et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res.
67, 6745–6752 (2007).
Shaw, R. J.
et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science
310, 1642–1646 (2005). This study was the first to link the effects of metformin on hepatic gluconeogenesis with LKB1-dependent AMPK activation.
Kalaany, N. Y. & Sabatini, D. M.
Tumours with PI3K activation are resistant to dietary restriction. Nature
458, 725–731 (2009).
Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K.
Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res.
69, 7507–7511 (2009).
et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J. Clin. Oncol.
27, 3297–3302 (2009).
et al. Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene
30, 1174–1182 (2011). This study showed that LKB1-deficient tumour cells are more sensitive to metformin, thus suggesting an AMPK activation-independent effect of metformin and indicating a patient population that might benefit from the drug.
Memmott, R. M.
et al. Metformin prevents tobacco carcinogen–induced lung tumorigenesis. Cancer Prev. Res. (Phila)
3, 1066–1076 (2010).
et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev. Res. (Phila)
3, 1077–1083 (2010).
Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev. Res. (Phila)
3, 1060–1065 (2010).
Maki, R. G.
Small is beautiful: insulin-like growth factors and their role in growth, development, and cancer. J. Clin. Oncol.
28, 4985–4995 (2010).
et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol. Cancer Ther.
9, 1286–1297 (2010).
Shaw, R. J. & Cantley, L. C.
Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature
441, 424–430 (2006).
et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell
39, 171–183 (2010). This paper presents a comprehensive genetic and metabolomic analysis of how mTORC1 signalling influences cell metabolism.
Engelman, J. A.
Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer
9, 550–562 (2009).
Garcia-Echeverria, C. & Sellers, W. R.
Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene
27, 5511–5526 (2008).
Locasale, J. W., Cantley, L. C. & Vander Heiden, M. G.
Cancer's insatiable appetite. Nature Biotech.
27, 916–917 (2009).
Stratton, M. R.
Exploring the genomes of cancer cells: progress and promise. Science
331, 1553–1558 (2011).
Engelman, J. A.
et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med.
14, 1351–1356 (2008). Although not the focus of this paper, this study linked responses by PET scanning to targeted therapy responses in genetically well-defined mouse models of lung cancer.
Holdsworth, C. H.
et al. CT and PET: early prognostic indicators of response to imatinib mesylate in patients with gastrointestinal stromal tumor. AJR Am. J. Roentgenol.
189, W324–W330 (2007).
et al. Glucose deprivation contributes to the development of kras pathway mutations in tumor cells. Science
325, 1555–1559 (2009). This study showed that a major selective force driving KRAS mutations was the requirement of tumours to take up adequate glucose.
Linardou, H., Dahabreh, I. J., Bafaloukos, D., Kosmidis, P. & Murray, S.
Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nature Rev. Clin. Oncol.
6, 352–366 (2009).
et al. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nature Rev. Clin. Oncol.
6, 519–527 (2009).
Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R. & Lazebnik, Y.
Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J. Cell Biol.
178, 93–105 (2007). This study was among the first to demonstrate that cancer cells can be dependent on glutamine, and identified a connection between MYC and this dependence.
Wise, D. R.
et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA
105, 18782–18787 (2008).
et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature
458, 762–765 (2009).
et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther.
7, 110–120 (2008).
et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA
94, 6658–6663 (1997). The paper reported a link between MYC and metabolism and identified LDHA as a potential target for cancer therapy.
et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA
107, 2037–2042 (2010).
Zhou, R., Vander Heiden, M. G. & Rudin, C. M.
Genotoxic exposure is associated with alterations in glucose uptake and metabolism. Cancer Res.
62, 3515–3520 (2002).
Scott, R. B.
Cancer chemotherapy — the first twenty-five years. BMJ
4, 259–265 (1970).
Chabner, B. A. & Roberts, T. G. Jr.
Timeline: chemotherapy and the war on cancer. Nature Rev. Cancer
5, 65–72 (2005).
Neuman, R. E. & McCoy, T. A.
Dual requirement of Walker carcinosarcoma 256 in vitro for asparagine and glutamine. Science
124, 124–125 (1956).
Derst, C., Henseling, J. & Rohm, K. H.
Engineering the substrate specificity of Escherichia coli asparaginase. II. Selective reduction of glutaminase activity by amino acid replacements at position 248. Protein Sci.
9, 2009–2017 (2000).
et al. Asparaginase-induced derangements of glutamine metabolism: the pathogenetic basis for some drug-related side-effects. Eur. J. Clin. Invest.
18, 512–516 (1988).
Curthoys, N. P. & Watford, M.
Regulation of glutaminase activity and glutamine metabolism. Annu. Rev. Nutr.
15, 133–159 (1995).
Bach, S. J. & Swaine, D.
The effect of arginase on the retardation of tumour growth. Br. J. Cancer
19, 379–386 (1965).
Ni, Y., Schwaneberg, U. & Sun, Z. H.
Arginine deiminase, a potential anti-tumor drug. Cancer Lett.
261, 1–11 (2008).
Yang, T. S.
et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br. J. Cancer
103, 954–960 (2010).
DeVita, V. T., Hellman, S. & Rosenberg, S. A.
Cancer, Principles and Practice of Oncology (Lippincott Williams & Wilkins, Philadelphia, 2005).
Potten, C. S., Kellett, M., Rew, D. A. & Roberts, S. A.
Proliferation in human gastrointestinal epithelium using bromodeoxyuridine in vivo: data for different sites, proximity to a tumour, and polyposis coli. Gut
33, 524–529 (1992).
Rew, D. A. & Wilson, G. D.
Cell production rates in human tissues and tumours and their significance. Part II: clinical data. Eur. J. Surg. Oncol.
26, 405–417 (2000).
et al. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc. Natl Acad. Sci. USA
106, 17413–17418 (2009).
Kumei, Y., Nakajima, T., Sato, A., Kamata, N. & Enomoto, S.
Reduction of G1 phase duration and enhancement of c-myc gene expression in HeLa cells at hypergravity. J. Cell Sci.
93, 221–226 (1989).
Brown, J. M. & Attardi, L. D.
The role of apoptosis in cancer development and treatment response. Nature Rev. Cancer
5, 231–237 (2005).
et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J. Clin. Oncol.
22, 3766–3775 (2004).
et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell
8, 311–321 (2005). This study was among the first to explore the targeting of a specific pathway required for cells to generate a biomass component other than DNA that is needed for cell growth.
Tainter, M. L., Cutting, W. C. & Stockton, A. B.
Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. Am. J. Public Health Nations Health
24, 1045–1053 (1934).
Kurhanewicz, J., Bok, R., Nelson, S. J. & Vigneron, D. B.
Current and potential applications of clinical13C MR spectroscopy. J. Nucl. Med.
49, 341–344 (2008).
New approaches for imaging tumour responses to treatment. Nature Rev. Cancer
8, 94–107 (2008). References 73 and 74 review the clinical use of 13C-MR spectroscopy as a technique to image metabolism in patients that could considerably aid the development of drugs targeting cancer metabolism.
Hanahan, D. & Weinberg, R. A.
The hallmarks of cancer. Cell
100, 57–70 (2000).
Jones, R. G. & Thompson, C. B.
Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev.
23, 537–548 (2009).
Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell. Metab.
3, 177–185 (2006).
Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C.
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell. Metab.
3, 187–197 (2006). The two studies reported in references 77 and 78 linked hypoxia signalling to inhibition of PDK, thus raising interest in targeting this metabolic node for cancer therapy.
Holness, M. J. & Sugden, M. C.
Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem. Soc. Trans.
31, 1143–1151 (2003).
et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell
11, 37–51 (2007).
Michelakis, E. D.
et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med.
2, 31ra34 (2010). This study showed that DCA can be given safely to patients with glioma and it can have effects on mitochondria in tumour cells, thus confirming that a therapeutic window can exist for agents targeting central metabolism.
et al. Over-expression of facilitative glucose transporter genes in human cancer. Biochem. Biophys. Res. Commun.
170, 223–230 (1990).
Macheda, M. L., Rogers, S. & Best, J. D.
Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell Physiol.
202, 654–662 (2005).
El Mjiyad, N., Caro-Maldonado, A., Ramirez-Peinado, S. & Munoz-Pinedo, C.
Sugar-free approaches to cancer cell killing. Oncogene
30, 253–264 (2011).
Aft, R. L., Zhang, F. W. & Gius, D.
Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br. J. Cancer
87, 805–812 (2002).
et al. Effects of 2-deoxyglucose on drug-sensitive and drug-resistant human breast cancer cells: toxicity and magnetic resonance spectroscopy studies of metabolism. Cancer Res.
50, 544–551 (1990).
Landau, B. R., Laszlo, J., Stengle, J. & Burk, D.
Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-D-glucose. J. Natl Cancer Inst.
21, 485–494 (1958). This clinical study exploring the use of 2DG in patients was arguably the first trial of an agent targeting increased glucose uptake in cancer.
Mohanti, B. K.
et al. Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int. J. Radiat. Oncol. Biol. Phys.
35, 103–111 (1996).
et al. Optimizing cancer radiotherapy with 2-deoxy-D-glucose dose escalation studies in patients with glioblastoma multiforme. Strahlenther. Onkol.
181, 507–514 (2005).
Dwarakanath, B. & Jain, V.
Targeting glucose metabolism with 2-deoxy-D-glucose for improving cancer therapy. Future Oncol.
5, 581–585 (2009).
Mathupala, S. P., Ko, Y. H. & Pedersen, P. L.
Hexokinase-2 bound to mitochondria: cancer's stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin. Cancer Biol.
19, 17–24 (2009).
et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med.
208, 313–326 (2011).
Robey, R. B. & Hay, N.
Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene
25, 4683–4696 (2006).
Galluzzi, L., Kepp, O., Tajeddine, N. & Kroemer, G.
Disruption of the hexokinase–VDAC complex for tumor therapy. Oncogene
27, 4633–4635 (2008).
Ko, Y. H.
et al. Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem. Biophys. Res. Commun.
324, 269–275 (2004).
Pereira da Silva, A. P.
et al. Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate. Biochem. J.
417, 717–726 (2009).
Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int. J. Biochem. Cell Biol.
43, 969–980 (2011).
et al. Isolation and characterization of the human pyruvate kinase M gene. Eur. J. Biochem.
198, 101–106 (1991).
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).
Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C.
Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature
452, 181–186 (2008). The studies in references 99 and 100 showed that PKM2 provides a selective advantage for tumour growth in vivo , and demonstrated a link between growth signalling and decreased PKM2 activity.
Spoden, G. A.
et al. Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation. Int. J. Cancer
123, 312–321 (2008).
Vander Heiden, M. G.
et al. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol.
79, 1118–1124 (2010).
Boxer, M. B.
et al. Evaluation of substituted N,N′-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. J. Med. Chem.
53, 1048–1055 (2010).
Jiang, J. K.
et al. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg Med. Chem. Lett.
20, 3387–3393 (2010).
Yalcin, A., Telang, S., Clem, B. & Chesney, J.
Regulation of glucose metabolism by 6-phosphofructo- 2-kinase/fructose-2,6-bisphosphatases in cancer. Exp. Mol. Pathol.
86, 174–179 (2009).
et al. High expression of inducible 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res.
62, 5881–5887 (2002).
et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene
25, 7225–7234 (2006). This study was among the first to link RAS transformation to glycolysis and proposed PFKFB3 as a target in RAS-transformed cells.
Marsin, A. S., Bouzin, C., Bertrand, L. & Hue, L.
The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J. Biol. Chem.
277, 30778–30783 (2002).
Manes, N. P. & El-Maghrabi, M. R.
The kinase activity of human brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is regulated via inhibition by phosphoenolpyruvate. Arch. Biochem. Biophys.
438, 125–136 (2005).
Dimmer, K. S., Friedrich, B., Lang, F., Deitmer, J. W. & Broer, S.
The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J.
350, 219–227 (2000).
Gallagher, S. M., Castorino, J. J., Wang, D. & Philp, N. J.
Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res.
67, 4182–4189 (2007).
Kennedy, K. M. & Dewhirst, M. W.
Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol.
6, 127–148 (2010).
et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest.
118, 3930–3942 (2008). This study proposed the idea that a symbiotic relationship can exist within tumours, with some cells using the lactate secreted by other cells as a fuel source.
Murray, C. M.
et al. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nature Chem. Biol.
1, 371–376 (2005).
Ovens, M. J., Manoharan, C., Wilson, M. C., Murray, C. M. & Halestrap, A. P.
The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem. J.
431, 217–225 (2010).
Halestrap, A. P. & Meredith, D.
The SLC16 gene family — from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch.
447, 619–628 (2004).
Fantin, V. R., St-Pierre, J. & Leder, P.
Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell
9, 425–434 (2006).
et al. Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. Biochem. Pharmacol.
62, 81–89 (2001).
Garten, A., Petzold, S., Korner, A., Imai, S. & Kiess, W.
Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol. Metab.
20, 130–138 (2009).
Hasmann, M. & Schemainda, I.
FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res.
63, 7436–7442 (2003).
et al. Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J. Biol. Chem.
285, 34106–34114 (2010).
et al. Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE. PLoS ONE
4, e7897 (2009).
Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A. R.
The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs
26, 45–51 (2008).
Burgos, E. S.
NAMPT in regulated NAD biosynthesis and its pivotal role in human metabolism. Curr. Med. Chem.
18, 1947–1961 (2011).
Parsons, D. W.
et al. An integrated genomic analysis of human glioblastoma multiforme. Science
321, 1807–1812 (2008). This paper reported the presence of IDH1 mutations in human cancer, sparking a flurry of research on the role of mutated IDH in cancer.
et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med.
360, 765–773 (2009).
Mardis, E. R.
et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med.
361, 1058–1066 (2009).
et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature
462, 739–744 (2009). This study showed that IDH mutations lead to a gain-of-function activity, thus suggesting that this enzyme could be a therapeutic target.
Ward, P. S.
et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell
17, 225–234 (2010).
et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med.
207, 339–344 (2010).
Verhaak, R. G.
et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell
17, 98–110 (2010).
et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol.
28, 2348–2355 (2010).
Figueroa, M. E.
et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell
18, 553–567 (2010). This study showed that mutations in IDH and TET2 are mutually exclusive in acute myeloid leukaemia, which suggests that mutations in IDH promote cancer by influencing chromatin structure and cellular differentiation.
et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell
19, 17–30 (2011).
et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep.
12, 463–469 (2011).
et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science
324, 930–935 (2009).
et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature
468, 839–843 (2010).
Tennant, D. A.
et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene
28, 4009–4021 (2009).
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). This paper was one of the first detailed characterizations of metabolism in cancer cells. Using NMR spectroscopy and13C-labelling, it demonstrated that glutamine can be an important nutrient for cancer cells to replenish metabolites that are depleted from the TCA cycle for biosynthesis.
Vousden, K. H.
Alternative fuel — another role for p53 in the regulation of metabolism. Proc. Natl Acad. Sci. USA
107, 7117–7118 (2010).
et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA
107, 7455–7460 (2010).
Wang, J. B.
et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell
18, 207–219 (2010). This study showed that the chemical inhibition of glutaminase can be used to selectively target cancer cells.
Seltzer, M. J.
et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res.
70, 8981–8987 (2010).
Ardawi, M. S. & Newsholme, E. A.
Glutamine metabolism in lymphocytes of the rat. Biochem. J.
212, 835–842 (1983).
Ookhtens, M., Kannan, R., Lyon, I. & Baker, N.
Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am. J. Physiol.
247, R146–R153 (1984).
Menendez, J. A. & Lupu, R.
Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer
7, 763–777 (2007).
Nomura, D. K.
et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell
140, 49–61 (2010).
Kuo, W., Lin, J. & Tang, T. K.
Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int. J. Cancer
85, 857–864 (2000).
Does G6PD deficiency protect against cancer? A critical review. J. Epidemiol. Community Health
41, 89–93 (1987).
Boros, L. G.
et al. Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism?
50, 55–59 (1998). This study was among the first modern studies to track carbon in cancer cells, and called into question common assumptions about cancer metabolism.
Shlomi, T., Benyamini, T., Gottlieb, E., Sharan, R. & Ruppin, E.
Genome-scale metabolic modeling elucidates the role of proliferative adaptation in causing the warburg effect. PLoS Comput. Biol.
7, e1002018 (2011).
et al. The action of pteroylglutamic conjugates on man. Science
106, 619–621 (1947).
Farber, S., Diamond, L. K., Mercer, R. D., Sylvester, R. F. & Wolff, J. A.
Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med.
238, 787–793 (1948). This classic paper reported the first clinical efficacy of a cancer therapy targeting metabolism.
Li, M. C., Hertz, R. & Bergenstal, D. M.
Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N. Engl. J. Med.
259, 66–74 (1958).
Jaffe, N., Frei, E., Traggis, D. & Bishop, Y.
Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N. Engl. J. Med.
291, 994–997 (1974).
Kidd, J. G.
Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum. J. Exp. Med.
98, 565–582 (1953).
Desamidation enzymatique de l'asparagine. Arch. Internat. Physiol.
19, 369–398 (1922).
Broome, J. D.
Evidence that the L-asparaginase activity of guinea pig serum is responsible for its antilymphoma effects. Nature
191, 1114–1115 (1961).
et al. E. coli
L-asparaginase in the treatment of leukemia and solid tumors in 131 children. Cancer
25, 306–320 (1970).
Larson, R. A.
et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood
85, 2025–2037 (1995).
Furuta, E., Okuda, H., Kobayashi, A. & Watabe, K.
Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim. Biophys. Acta
1805, 141–152 (2010).
Dang, C. V.
Glutaminolysis: supplying carbon or nitrogen or both for cancer cells?
9, 3884–3886 (2010).
Locasale, J. W.
et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet.
31 Jul 2011 (doi:10.1038/ng.890).
et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature
14 Jul 2011 (doi:10.1038/nature10350).
Flavin, R., Peluso, S., Nguyen, P. L. & Loda, M.
Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol.
6, 551–562 (2010).
Bauer, D. E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C. B.
ATP citrate lyase is an important component of cell growth and transformation. Oncogene
24, 6314–6322 (2005).
Chajes, V., Cambot, M., Moreau, K., Lenoir, G. M. & Joulin, V.
Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Res.
66, 5287–5294 (2006).
Evans, M. J., Saghatelian, A., Sorensen, E. J. & Cravatt, B. F.
Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Nature Biotech.
23, 1303–1307 (2005).
et al. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res.
69, 7986–7993 (2009).
et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA
108, 8674–8679 (2011).
et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev.
25, 1041–1051 (2011).