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Mechanisms of Disease: the PI3K–Akt–PTEN signaling node—an intercept point for the control of angiogenesis in brain tumors

Nature Clinical Practice Neurology volume 3, pages 682–693 (2007)Cite this article

Abstract

The overall prognosis for patients with high-grade glioma remains dismal, despite advances in treatment modalities including neurosurgery, radiation therapy and conventional cytotoxic chemotherapy. In this article, we review literature that provides a rationale for the use of antiangiogenic therapy to improve the treatment of high-grade neoplasms in the CNS. In particular, we focus our discussion on the central role of the phosphatidylinositol 3-kinase–Akt– phosphatase and tensin homolog (PI3K–Akt–PTEN) axis as a potential molecular target for the control of angiogenesis in brain tumors via the coordinated control of cell division, tumor growth, angiogenesis, apoptosis, invasion and cellular metabolism in the tumor and stromal compartments. We suggest that instead of inhibiting a single cell surface receptor, thereby leaving other receptors free to pulse survival, proliferative, angiogenic and invasive signals, a more effective way to approach the design of targeted therapy against brain tumors is to inhibit a nodal point where redundant cell surface receptor signals converge to transmit important, relatively conserved signaling events within the cell. The epigenetic and post-translational regulation of PI3K–Akt–PTEN signaling has a prominent role in brain tumor pathogenesis, and we therefore suggest that PI3K could be an important target for therapies that target brain tumors.

Key Points

  • Findings in high-grade glioma, including high microvessel density and increased expression of proangiogenic factors, suggest that angiogenesis has an important role in the pathogenesis and progression of high-grade tumors

  • Signaling through phosphatidylinositol 3-kinase (PI3K) pathways in the tumor and stromal compartments provides a crucial nodal point for the control of angiogenesis and tumor progression

  • Signaling through the PI3K–Akt intercept node is required to mount an appropriate angiogenic response, but this signaling must be tightly regulated to permit proper development and to prevent inappropriate angiogenesis

  • It is becoming increasingly apparent that the most effective targeted therapeutic agents against high-grade gliomas are likely to be inhibitors that block multiple target kinases

  • It is hoped that small-molecule inhibitors that target major intercept nodes involved in tumor progression and angiogenic response will be successful alone or in combination with current treatment modalities in effecting durable responses and improving survival in adult patients with brain tumors

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Figure 1: The PI3K–Akt–PTEN intercept node is a central regulator of angiogenesis in brain tumors.

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References

  1. Newton HB (2004) Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis. Expert Rev Anticancer Ther 4: 105–128

    Article  CAS  PubMed  Google Scholar 

  2. Sathornsumetee S and Rich JN (2006) New approaches to primary brain tumor treatment. Anticancer Drugs 17: 1003–1016

    Article  CAS  PubMed  Google Scholar 

  3. Davis FG and McCarthy BJ (2001) Current epidemiological trends and surveillance issues in brain tumors. Expert Rev Anticancer Ther 1: 395–401

    Article  CAS  PubMed  Google Scholar 

  4. Wen PY and Loeffler JS (1999) Management of brain metastases. Oncology (Williston Park) 13: 941–954, 957–961

    CAS  Google Scholar 

  5. Lacroix M et al. (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95: 190–198

    Article  CAS  PubMed  Google Scholar 

  6. Reardon DA and Wen PY (2006) Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist 11: 152–164

    Article  CAS  PubMed  Google Scholar 

  7. Brandes AA (2003) State-of-the-art treatment of high-grade brain tumors. Semin Oncol 30: 4–9

    Article  PubMed  Google Scholar 

  8. Grossman SA and Batara JF (2004) Current management of glioblastoma multiforme. Semin Oncol 31: 635–644

    Article  CAS  PubMed  Google Scholar 

  9. Newton HB et al. (1999) Clinical presentation, diagnosis, and pharmacotherapy of patients with primary brain tumors. Ann Pharmacother 33: 816–832

    Article  CAS  PubMed  Google Scholar 

  10. Fine HA et al. (1993) Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71: 2585–2597

    Article  CAS  PubMed  Google Scholar 

  11. Stupp R et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987–996

    Article  CAS  PubMed  Google Scholar 

  12. Taphoorn MJ et al. (2005) Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 6: 937–944

    Article  PubMed  Google Scholar 

  13. Wen S et al. (2001) PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci USA 98: 4 622–4627

    Google Scholar 

  14. Liotta LA and Kohn EC (2001) The microenvironment of the tumour–host interface. Nature 411: 375–379

    Article  CAS  PubMed  Google Scholar 

  15. Mueller MM and Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4: 839–849

    Article  CAS  PubMed  Google Scholar 

  16. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186

    Article  CAS  PubMed  Google Scholar 

  17. Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175: 409–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Folkman J et al. (1991) Duodenal ulcer: discovery of a new mechanism and development of angiogenic therapy that accelerates healing. Ann Surg 214: 414–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fang J et al. (2000) Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci USA 97: 3884–3889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dameron KM et al. (1994) Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265: 1582–1584

    Article  CAS  PubMed  Google Scholar 

  21. Good DJ et al. (1990) A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci USA 87: 6624–6628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364

    Article  CAS  PubMed  Google Scholar 

  23. Plate KH et al. (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359: 845–848

    Article  CAS  PubMed  Google Scholar 

  24. Schmidt NO et al. (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int J Cancer 84: 10–18

    Article  CAS  PubMed  Google Scholar 

  25. Salmaggi A et al. (2003) Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol 62: 297–303

    Article  PubMed  Google Scholar 

  26. Tso CL et al. (2006) Distinct transcription profiles of primary and secondary glioblastoma subgroups. Cancer Res 66: 159–167

    Article  CAS  PubMed  Google Scholar 

  27. Rege TA et al. (2005) Endogenous inhibitors of angiogenesis in malignant gliomas: nature's antiangiogenic therapy. Neuro Oncol 7: 106–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brem S et al. (1992) Immunolocalization of basic fibroblast growth factor to the microvasculature of human brain tumors. Cancer 70: 2673–2680

    Article  CAS  PubMed  Google Scholar 

  29. Plate KH et al. (1995) Angiogenesis in malignant gliomas. Glia 15: 339–347

    Article  CAS  PubMed  Google Scholar 

  30. Vajkoczy P et al. (2002) Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest 109: 777–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leon SP et al. (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372

    Article  CAS  PubMed  Google Scholar 

  32. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296: 1655–1657

    Article  CAS  PubMed  Google Scholar 

  33. Kita D et al. (2007) PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol (Berl) 113: 295–302

    Article  CAS  Google Scholar 

  34. Samuels Y et al. (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554

    Article  CAS  PubMed  Google Scholar 

  35. Gallia GL et al. (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4: 709–714

    Article  CAS  PubMed  Google Scholar 

  36. Omuro AM et al. (2007) Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 6: 1909–1919

    Article  CAS  PubMed  Google Scholar 

  37. Hood JD and Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2: 91–100

    Article  PubMed  Google Scholar 

  38. Zoppi N et al. (2007) The FN13 peptide inhibits human tumor cells invasion through the modulation of αvβ3 integrins organization and the inactivation of ILK pathway. Biochim Biophys Acta 1773: 747–763

    Article  CAS  PubMed  Google Scholar 

  39. Persad S et al. (2000) Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA 97: 3207–3212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Obara S et al. (2004) Integrin-linked kinase (ILK) regulation of the cell viability in PTEN mutant glioblastoma and in vitro inhibition by the specific COX-2 inhibitor NS-398. Cancer Lett 208: 115–122

    Article  CAS  PubMed  Google Scholar 

  41. Delcommenne M et al. (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 95: 11211–11216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Koul D et al. (2005) Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. Mol Cancer Ther 4: 1681–1688

    Article  CAS  PubMed  Google Scholar 

  43. Lawlor MA and Alessi DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114: 2903–2910

    CAS  PubMed  Google Scholar 

  44. Brazil DP et al. (2002) PKB binding proteins: getting in on the Akt. Cell 111: 293–303

    Article  CAS  PubMed  Google Scholar 

  45. Sarbassov DD et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307: 1098–1101

    Article  CAS  PubMed  Google Scholar 

  46. Haas-Kogan D et al. (1998) Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8: 1195–1198

    Article  CAS  PubMed  Google Scholar 

  47. Choe G et al. (2003) Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63: 2742–2746

    CAS  PubMed  Google Scholar 

  48. Malstrom S et al. (2001) Tumor induction by an Lck-MyrAkt transgene is delayed by mechanisms controlling the size of the thymus. Proc Natl Acad Sci USA 98: 14967–14972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Majumder PK et al. (2003) Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci USA 100: 7841–7846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Trotman LC et al. (2006) Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Denning G et al. (2007) A short N-terminal sequence of PTEN controls cytoplasmic localization and is required for suppression of cell growth. Oncogene 26: 3930–3940

    Article  CAS  PubMed  Google Scholar 

  52. Jiang BH et al. (2000) Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 97: 1749–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sun JF et al. (2005) Microvascular patterning is controlled by fine-tuning the Akt signal. Proc Natl Acad Sci USA 102: 128–133

    Article  CAS  PubMed  Google Scholar 

  54. Phung TL et al. (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10: 159–170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ackah E et al. (2005) Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest 115: 2119–2127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen J et al. (2005) Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 11: 1188–1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Maehama T and Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375–13378

    Article  CAS  PubMed  Google Scholar 

  58. Andjelkovic M et al. (1996) Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci USA 93: 5699–5704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Brognard J et al. (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25: 917–931

    Article  CAS  PubMed  Google Scholar 

  60. Gao T et al. (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18: 13–24

    Article  CAS  PubMed  Google Scholar 

  61. Forgacs E et al. (1998) Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 17: 1557–1565

    Article  CAS  PubMed  Google Scholar 

  62. Maehama T and Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9: 125–128

    Article  CAS  PubMed  Google Scholar 

  63. Wishart MJ and Dixon JE (2002) PTEN and myotubularin phosphatases: from 3-phosphoinositide dephosphorylation to disease. Trends Cell Biol 12: 579–585

    Article  CAS  PubMed  Google Scholar 

  64. Steck PA et al. (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362

    Article  CAS  PubMed  Google Scholar 

  65. Li J et al. (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947

    Article  CAS  PubMed  Google Scholar 

  66. Rasheed BK et al. (1997) PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 57: 4187–4190

    CAS  PubMed  Google Scholar 

  67. Wang SI et al. (1997) Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57: 4183–4186

    CAS  PubMed  Google Scholar 

  68. Di Cristofano A et al. (1998) Pten is essential for embryonic development and tumour suppression. Nat Genet 19: 348–355

    Article  CAS  PubMed  Google Scholar 

  69. Podsypanina K et al. (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 96: 1563–1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhou XP et al. (2000) Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet 9: 765–768

    Article  CAS  PubMed  Google Scholar 

  71. Liaw D et al. (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16: 64–67

    Article  CAS  PubMed  Google Scholar 

  72. Mayo LD and Donner DB (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98: 11598–11603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Su JD et al. (2003) PTEN and phosphatidylinositol 3′-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment. Cancer Res 63: 3585–3592

    CAS  PubMed  Google Scholar 

  74. Hirota K and Semenza GL (2006) Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 59: 15–26

    Article  PubMed  Google Scholar 

  75. Stohrer M et al. (2000) Oncotic pressure in solid tumors is elevated. Cancer Res 60: 4251–4255

    CAS  PubMed  Google Scholar 

  76. Zhong H et al. (1999) Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59: 5830–5835

    CAS  PubMed  Google Scholar 

  77. Semenza GL (2004) Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell 5: 405–406

    Article  CAS  PubMed  Google Scholar 

  78. Zundel W et al. (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14: 391–396

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhong H et al. (2000) Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545

    CAS  PubMed  Google Scholar 

  80. Pore N et al. (2006) Akt1 activation can augment hypoxia-inducible factor-1α expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res 4: 471–479

    Article  CAS  PubMed  Google Scholar 

  81. Warburg O (1956) On the origin of cancer cells. Science 123: 309–314

    Article  CAS  PubMed  Google Scholar 

  82. Gottlieb E and Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5: 857–866

    Article  CAS  PubMed  Google Scholar 

  83. Elstrom RL et al. (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64: 3892–3899

    Article  CAS  PubMed  Google Scholar 

  84. Kim JW and Dang CV (2006) Cancer's molecular sweet tooth and the Warburg effect. Cancer Res 66: 8927–8930

    Article  CAS  PubMed  Google Scholar 

  85. Jin S et al. (2007) Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120: 379–383

    Article  CAS  PubMed  Google Scholar 

  86. Guicciardi ME et al. (2004) Lysosomes in cell death. Oncogene 23: 2881–2890

    Article  CAS  PubMed  Google Scholar 

  87. Jaattela M (2004) Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene 23: 2746–2756

    Article  CAS  PubMed  Google Scholar 

  88. Joyce JA et al. (2004) Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5: 443–453

    Article  CAS  PubMed  Google Scholar 

  89. Kroemer G and Jaattela M (2005) Lysosomes and autophagy in cell death control. Nat Rev Cancer 5: 886–897

    Article  CAS  PubMed  Google Scholar 

  90. Mohanam S et al. (2001) Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene 20: 3665–3673

    Article  CAS  PubMed  Google Scholar 

  91. Vredenburgh JJ et al. (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13: 1253–1259

    Article  CAS  PubMed  Google Scholar 

  92. Iwamaru A et al. (2007) Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene 26: 1840–1851

    Article  CAS  PubMed  Google Scholar 

  93. Purow B and Fine HA (2004) Progress report on the potential of angiogenesis inhibitors for neuro-oncology. Cancer Invest 22: 577–587

    Article  CAS  PubMed  Google Scholar 

  94. Fine HA et al. (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18: 708–715

    Article  CAS  PubMed  Google Scholar 

  95. Vlahos CJ et al. (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269: 5241–5248

    CAS  PubMed  Google Scholar 

  96. Nutley BP et al. (2001) Pharmacokinetics and metabolism of the phosphatidylinositol 3-kinase inhibitor LY294002 in the mouse. Presented at the 92nd Annual Meeting of the American Association for Cancer Research, March 24–28, 2001, New Orleans, LA

  97. Schultz RM et al. (1995) In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 15: 1135–1139

    CAS  PubMed  Google Scholar 

  98. Zhu T et al. (2006) Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models. J Med Chem 49: 1373–1378

    Article  CAS  PubMed  Google Scholar 

  99. Fan QW et al. (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9: 341–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Raynaud FI et al. (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 67: 5840–5850

    Article  CAS  PubMed  Google Scholar 

  101. Ihle NT et al. (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3: 763–772

    CAS  PubMed  Google Scholar 

  102. Yaguchi S et al. (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 98: 545–556

    Article  CAS  PubMed  Google Scholar 

  103. Geng L et al. (2004) A specific antagonist of the p110δ catalytic component of phosphatidylinositol 3′-kinase, IC486068, enhances radiation-induced tumor vascular destruction. Cancer Res 64: 4893–4899

    Article  CAS  PubMed  Google Scholar 

  104. Garlich JR et al.: A vascular targeted pan PI-3 kinase prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res, in press

  105. Carpten JD et al. (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448: 439–444

    Article  CAS  PubMed  Google Scholar 

  106. Baselga J (2006) Targeting tyrosine kinases in cancer: the second wave. Science 312: 1175–1178

    Article  CAS  PubMed  Google Scholar 

  107. Paez JG et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500

    Article  CAS  PubMed  Google Scholar 

  108. Wong S and Witte ON (2004) The BCR–ABL story: bench to bedside and back. Annu Rev Immunol 22: 247–306

    Article  CAS  PubMed  Google Scholar 

  109. Wilhelm SM et al. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64: 7099–7109

    Article  CAS  PubMed  Google Scholar 

  110. Walker EH et al. (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6: 909–919

    Article  CAS  PubMed  Google Scholar 

  111. Brunet A et al. (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K–Akt signaling pathway. Curr Opin Neurobiol 11: 297–305

    Article  CAS  PubMed  Google Scholar 

  112. Romashkova JA and Makarov SS (1999) NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401: 86–90

    Article  CAS  PubMed  Google Scholar 

  113. Ozes ON et al. (1999) NF-κB activation by tumour necrosis factor requires the Akt serine–threonine kinase. Nature 401: 82–85

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by funding from NIH grant CA94233, Georgia Cancer Coalition, Semafore Pharmaceuticals, Aflac Cancer Center, and Cure Childhood Cancer Foundation (DLD); and Stephanie Lee Kramer/American Brain Tumor Association Translational Research Grant and Alex's Lemonade Stand Young Investigator Award (RCC).

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  1. RC Castellino is an Instructor of Pediatrics at Emory University and the Aflac Cancer Center and Blood Disorders Service in Atlanta, and DL Durden is the Aflac Endowed Chair of Basic and Translational Research at Emory University, Atlanta, GA, USA.,

    Robert C Castellino & Donald L Durden

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Correspondence to Donald L Durden.

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RC Castellino declared no competing interests. DL Durden is the scientific founder of, a consultant for, and a stockholder in Semafore Pharmaceuticals.

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Castellino, R., Durden, D. Mechanisms of Disease: the PI3K–Akt–PTEN signaling node—an intercept point for the control of angiogenesis in brain tumors. Nat Rev Neurol 3, 682–693 (2007). https://doi.org/10.1038/ncpneuro0661

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