Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding (original) (raw)
Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28:177–83. ArticlePubMedCAS Google Scholar
Groszer M, Erickson R, Scripture-Adams DD, Dougherty JD, Le Belle J, Zack JA, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci USA. 2006;103:111–6. ArticlePubMedCAS Google Scholar
Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen A-J, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455:1129–33. ArticlePubMedCAS Google Scholar
Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE, et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell. 2009;15:514–26. ArticlePubMedCAS Google Scholar
Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:357–61. ArticlePubMedCAS Google Scholar
Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol. 2005;23:5294–304. ArticlePubMedCAS Google Scholar
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74. PubMedCAS Google Scholar
Gulati N, Karsy M, Albert L, Murali R, Jhanwar-Uniyal M. Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. Int J Oncol. 2009;35:731–40. PubMedCAS Google Scholar
Albert L, Karsy M, Murali R, Jhanwar-Uniyal M. Inhibition of mTOR activates the MAPK pathway in glioblastoma multiforme. CANCER GENOMICS PROTEOMICS. 2009;6:255–61. PubMedCAS Google Scholar
Akhavan D, Cloughesy TF, Mischel PS. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro-Oncology. 2010;12:882–9. ArticlePubMedCAS Google Scholar
Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS. mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg. 2009;6:47–55. ArticlePubMedCAS Google Scholar
Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US). Cited 2013 Feb 14.
Levine AJ, Feng Z, Mak TW, You H, Jin S. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 2006;20:267–75. ArticlePubMedCAS Google Scholar
Feng Z. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol. 2010;2:a001057. ArticlePubMedCAS Google Scholar
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501. ArticlePubMedCAS Google Scholar
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8. ArticleCAS Google Scholar
Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12. ArticlePubMedCAS Google Scholar
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. ArticlePubMedCAS Google Scholar
Holland EC. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet. 2001;2:120–9. ArticlePubMedCAS Google Scholar
Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008;27:5416–30. ArticlePubMedCAS Google Scholar
Bellacosa A, Testa JR, Moore R, Larue L. A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther. 2004;3:268–75. ArticlePubMedCAS Google Scholar
Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol. 2003;4:117–26. ArticlePubMedCAS Google Scholar
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34. ArticlePubMedCAS Google Scholar
Dowling RJO, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 1804;2010:433–9. Google Scholar
Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006;314:467–71. ArticlePubMedCAS Google Scholar
Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127:125–37. ArticlePubMedCAS Google Scholar
Volarević S, Thomas G. Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucleic Acid Res Mol Biol. 2001;65:101–27. ArticlePubMed Google Scholar
Sonenberg N, Gingras AC. The mRNA 5′ cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol. 1998;10:268–75. ArticlePubMedCAS Google Scholar
De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23:3189–99. ArticlePubMedCAS Google Scholar
Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 2007;318:977–80. ArticlePubMedCAS Google Scholar
Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol. 2004;14:1650–6. ArticlePubMedCAS Google Scholar
Feng Z, Hu W, de Stanchina E, Teresky AK, Jin S, Lowe S, et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 2007;67:3043–53. ArticlePubMedCAS Google Scholar
Kong M, Fox CJ, Mu J, Solt L, Xu A, Cinalli RM, et al. The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis. Science. 2004;306:695–8. ArticlePubMedCAS Google Scholar
Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan K-L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 2004;18:1533–8. ArticlePubMedCAS Google Scholar
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11:859–71. ArticlePubMedCAS Google Scholar
Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 1995;377:646–9. ArticlePubMedCAS Google Scholar
Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, et al. Regulation of PTEN transcription by p53. Molecular Cell. 2001;8:317–25. ArticlePubMedCAS Google Scholar
Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134:451–60. ArticlePubMedCAS Google Scholar
Knobbe CB, Merlo A, Reifenberger G. Pten signaling in gliomas. Neuro-Oncology. 2002;4:196–211. PubMedCAS Google Scholar
Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol. 1998;57:684–9. ArticlePubMedCAS Google Scholar
Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, et al. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res. 2001;7:2387–95. PubMedCAS Google Scholar
Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H. PTEN methylation and expression in glioblastomas. Acta Neuropathol. 2003;106:479–85. ArticlePubMedCAS Google Scholar
Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamgüney T, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro-Oncology. 2007;9:271–9. ArticlePubMedCAS Google Scholar
Karsy M, Arslan E, Moy F. Current progress on understanding microRNAs in glioblastoma multiforme. Genes Cancer. 2012;3:3–15. ArticlePubMed Google Scholar
Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001;29:396–403. ArticlePubMedCAS Google Scholar
Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science. 2001;294:2186–9. ArticlePubMedCAS Google Scholar
Marino S, Krimpenfort P, Leung C, van der Korput HAGM, Trapman J, Camenisch I, et al. PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development. 2002;129:3513–22. PubMedCAS Google Scholar
Downward J. Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells. Oncogene. 2004;23:8376–83. ArticlePubMedCAS Google Scholar
Karsy M, Albert L, Tobias ME, Murali R, Jhanwar-Uniyal M. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010;30:4915–20. PubMedCAS Google Scholar
Furnari FB, Huang HJ, Cavenee WK. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res. 1998;58:5002–8. PubMedCAS Google Scholar
Gottschalk AR, Basila D, Wong M, Dean NM, Brandts CH, Stokoe D, et al. p27Kip1 is required for PTEN-induced G1 growth arrest. Cancer Res. 2001;61:2105–11. PubMedCAS Google Scholar
Wen S, Stolarov J, Myers MP, Su JD, Wigler MH, Tonks NK, et al. PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci USA. 2001;98:4622–7. ArticlePubMedCAS Google Scholar
Kubiatowski T, Jang T, Lachyankar MB, Salmonsen R, Nabi RR, Quesenberry PJ, et al. Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. J Neurosurg. 2001;95:480–8. ArticlePubMedCAS Google Scholar
Koul D, Parthasarathy R, Shen R, Davies MA, Jasser SA, Chintala SK, et al. Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene. 2001;20:6669–78. ArticlePubMedCAS Google Scholar
Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot. 1975;28:721–6. ArticlePubMed Google Scholar
Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Friedman AH, Herndon JE, et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neurooncol. 2010;96:219–30. ArticlePubMedCAS Google Scholar
Kreisl TN, Lassman AB, Mischel PS, Rosen N, Scher HI, Teruya-Feldstein J, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol. 2009;92:99–105. ArticlePubMedCAS Google Scholar
Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–11. ArticlePubMedCAS Google Scholar
Reardon DA, Wen PY, Alfred Yung WK, Berk L, Narasimhan N, Turner CD, et al. Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose trial. Cancer Chemother Pharmacol. 2012;69:849–60. ArticlePubMedCAS Google Scholar
Sarbassov DD, Ali SM, Sengupta S, Sheen J-H, Hsu PP, Bagley AF, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell. 2006;22:159–68. ArticlePubMedCAS Google Scholar
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5:671–88. ArticlePubMedCAS Google Scholar
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol. 2004;166:213–23. ArticlePubMedCAS Google Scholar
Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M, Holland EC. mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia. 2005;7:356–68. ArticlePubMedCAS Google Scholar
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263–84. ArticlePubMedCAS Google Scholar
Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem. 2009;284:8023–32. ArticlePubMedCAS Google Scholar
Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111:379–82. ArticlePubMedCAS Google Scholar
Molina JR, Hayashi Y, Stephens C, Georgescu M-M. Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia. 2010;12:453–63. PubMedCAS Google Scholar
Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle. 2009;8:3831–7. ArticlePubMedCAS Google Scholar
Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27:579–84. ArticlePubMedCAS Google Scholar
Schwer AL, Kavanagh BD, McCammon R, Gaspar LE, Kleinschmidt-De Masters BK, Stuhr K, et al. Radiographic and histopathologic observations after combined EGFR inhibition and hypofractionated stereotactic radiosurgery in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009;73:1352–7. ArticlePubMedCAS Google Scholar
Brown PD, Krishnan S, Sarkaria JN, Wu W, Jaeckle KA, Uhm JH, et al. Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol. 2008;26:5603–9. ArticlePubMedCAS Google Scholar
Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res. 2007;67:11712–20. ArticlePubMedCAS Google Scholar
Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97:880–7. ArticlePubMedCAS Google Scholar
Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, et al. Combination of temsirolimus (CCI-779) with chemoradiation in newly diagnosed glioblastoma multiforme (GBM) (NCCTG trial N027D) is associated with increased infectious risks. Clin Cancer Res. 2010;16:5573–80. ArticlePubMedCAS Google Scholar
Sarkaria JN, Galanis E, Wu W, Peller PJ, Giannini C, Brown PD, et al. North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2011;81:468–75. ArticlePubMedCAS Google Scholar
Cheng CK, Fan Q-W, Weiss WA. PI3K signaling in glioma—animal models and therapeutic challenges. Brain Pathol. 2009;19:112–20. ArticlePubMedCAS Google Scholar
Hayakawa M, Kaizawa H, Moritomo H, Koizumi T, Ohishi T, Yamano M, et al. Synthesis and biological evaluation of pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem Lett. 2007;17:2438–42. ArticlePubMedCAS Google Scholar
Fan Q-W, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007;67:7960–5. ArticlePubMedCAS Google Scholar
Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008;51:5522–32. ArticlePubMedCAS Google Scholar
García-Martínez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J. 2009;421:29–42. ArticlePubMedCAS Google Scholar
Liu T-J, Koul D, LaFortune T, Tiao N, Shen RJ, Maira S-M, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther. 2009;8:2204–10. ArticlePubMedCAS Google Scholar
Serra V, Markman B, Scaltriti M, Eichhorn PJA, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68:8022–30. ArticlePubMedCAS Google Scholar
Fan Q-W, Weiss WA. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol. 2012;821:349–59. ArticlePubMedCAS Google Scholar
Fan Q-W, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal. 2010;3:ra81. ArticlePubMedCAS Google Scholar
Westhoff M-A, Kandenwein JA, Karl S, Vellanki SHK, Braun V, Eramo A, et al. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene. 2009;28:3586–96. ArticlePubMedCAS Google Scholar
Xing W-J, Zou Y, Han Q-L, Dong Y-C, Deng Z-L, Lv X-H, et al. Effects of EGFR and PTEN gene expressions on the inhibition of U87MG glioblastoma cell proliferation induced by protein kinase inhibitors. Clin Exp Pharmacol Physiol. 2012;40:13–21. Google Scholar
Maira S-M, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7:1851–63. ArticlePubMedCAS Google Scholar
Sunayama J, Matsuda K-I, Sato A, Tachibana K, Suzuki K, Narita Y, et al. Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells. Stem Cells. 2010;28:1930–9. ArticlePubMedCAS Google Scholar
Sunayama J, Sato A, Matsuda K-I, Tachibana K, Suzuki K, Narita Y, et al. Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells. Neuro-Oncology. 2010;12:1205–19. PubMedCAS Google Scholar
Mukherjee B, Tomimatsu N, Amancherla K, Camacho CV, Pichamoorthy N, Burma S. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia. 2012;14:34–43. PubMedCAS Google Scholar
Cerniglia GJ, Karar J, Tyagi S, Christofidou-Solomidou M, Rengan R, Koumenis C, et al. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol. 2012;82:1230–40. ArticlePubMedCAS Google Scholar
Prasad G, Sottero T, Yang X, Mueller S, James CD, Weiss WA, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro-Oncology. 2011;13:384–92. ArticlePubMedCAS Google Scholar
Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, et al. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011;17:3193–203. ArticlePubMedCAS Google Scholar
Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70:288–98. ArticlePubMedCAS Google Scholar
Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 2010;70:621–31. ArticlePubMedCAS Google Scholar
McDowell KA, Riggins GJ, Gallia GL. Targeting the AKT pathway in glioblastoma. Curr Pharm Des. 2011;17:2411–20. ArticlePubMedCAS Google Scholar
Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J. 2007;404:15–21. ArticlePubMedCAS Google Scholar
Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408:297–315. ArticlePubMedCAS Google Scholar
Opel D, Westhoff M-A, Bender A, Braun V, Debatin K-M, Fulda S. Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res. 2008;68:6271–80. ArticlePubMedCAS Google Scholar
Chen L, Han L, Shi Z, Zhang K, Liu Y, Zheng Y, et al. LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway. Mol Med Report. 2012;5:575–9. CAS Google Scholar
Fedrigo CA, Grivicich I, Schunemann DP, Chemale IM, dos Santos D, Jacovas T, et al. Radioresistance of human glioma spheroids and expression of HSP70, p53 and EGFr. Radiat Oncol. 2011;6:156. ArticlePubMedCAS Google Scholar
Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther. 2004;3:763–72. PubMedCAS Google Scholar
Koul D, Shen R, Kim Y-W, Kondo Y, Lu Y, Bankson J, et al. Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro-Oncology. 2010;12:559–69. ArticlePubMedCAS Google Scholar
Gwak H-S, Shingu T, Chumbalkar V, Hwang Y-H, DeJournett R, Latha K, et al. Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer. 2011;128:787–96. ArticlePubMedCAS Google Scholar
Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, et al. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther. 2007;6:2505–14. ArticlePubMedCAS Google Scholar
Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N, et al. Antitumor activity of NVP-BKM120—a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res. 2012;18:184–95. ArticlePubMedCAS Google Scholar
Momota H, Nerio E, Holland EC. Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. Cancer Res. 2005;65:7429–35. ArticlePubMedCAS Google Scholar
Coppola JM, Ross BD, Rehemtulla A. Noninvasive imaging of apoptosis and its application in cancer therapeutics. Clin Cancer Res. 2008;14:2492–501. ArticlePubMedCAS Google Scholar
Becher OJ, Hambardzumyan D, Walker TR, Helmy K, Nazarian J, Albrecht S, et al. Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res. 2010;70:2548–57. ArticlePubMedCAS Google Scholar
Pitter KL, Galbán CJ, Galbán S, Tehrani OS, Saeed-Tehrani O, Li F, et al. Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. PLoS One. 2011;6:e14545. ArticlePubMedCAS Google Scholar
Salphati L, Heffron TP, Alicke B, Nishimura M, Barck K, Carano RA, et al. Targeting the PI3K pathway in the brain—efficacy of a PI3K inhibitor optimized to cross the blood–brain barrier. Clin Cancer Res. 2012;18:6239–48. ArticlePubMedCAS Google Scholar
Enzenmüller S, Gonzalez P, Karpel-Massler G, Debatin K-M, Fulda S. GDC-0941 enhances the lysosomal compartment via TFEB and primes glioblastoma cells to lysosomal membrane permeabilization and cell death. Cancer Letters. 2012;329:27–36. Google Scholar
Tanaka H, Yoshida M, Tanimura H, Fujii T, Sakata K, Tachibana Y, et al. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011;17:3272–81. ArticlePubMedCAS Google Scholar
Norman MH, Andrews KL, Bo YY, Booker SK, Caenepeel S, Cee VJ, et al. Selective class I phosphoinositide 3-kinase inhibitors: optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511. J Med Chem. 2012;55:7796–816. ArticlePubMedCAS Google Scholar
Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, et al. Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). J Med Chem. 2011;54:7105–26. ArticlePubMedCAS Google Scholar
Luk SK, Piekorz RP, Nürnberg B, Tony To S-S. The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma cell migration and invasion. Eur J Cancer. 2012;48:149–57. ArticlePubMedCAS Google Scholar
Mielcke TR, Mascarello A, Filippi-Chiela E, Zanin RF, Lenz G, Leal PC, et al. Activity of novel quinoxaline-derived chalcones on in vitro glioma cell proliferation. Eur J Med Chem. 2012;48:255–64. ArticlePubMedCAS Google Scholar
Xue Q, Hopkins B, Perruzzi C, Udayakumar D, Sherris D, Benjamin LE. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res. 2008;68:9551–7. ArticlePubMedCAS Google Scholar