Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 4/2013

01-08-2013 | Review

Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding

Authors: Arshawn Sami, Michael Karsy

Published in: Tumor Biology | Issue 4/2013

Login to get access

Abstract

Glioblastoma multiforme (GBM) is a grade IV astrocytoma with a median survival of 12 months despite current multi-modal treatment options. GBM is distinguished clinicopathologically into primary and secondary subtypes. Mutations of phosphatase and tensin homolog, and subsequent upregulation of the downstream protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway, are commonly seen in primary GBM and less predominantly in secondary GBM. While investigations into targeted treatments of mTOR have been attempted, feedback regulation within the mTOR signaling pathway may account for therapeutic resistance. Currently, rapamycin analogs, dual-targeted mTOR complex 1 and 2 agents as well as dual mTOR and phosphatidylinositol-3 kinase-targeted agents are being investigated experimentally and in clinical trials. This review will discuss the experimental potential of these agents in the treatment of GBM and their current stage in the GBM drug pipeline. Knowledge obtained from the application of these agents can help in understanding the pathogenesis of GBM as well as delineating subsequent treatment strategies.
Literature
1.
Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28:177–83.PubMedCrossRef
2.
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.PubMedCrossRef
3.
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.PubMedCrossRef
4.
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.PubMedCrossRef
5.
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.PubMedCrossRef
6.
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.PubMedCrossRef
7.
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.PubMed
8.
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.PubMed
9.
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.PubMed
10.
Akhavan D, Cloughesy TF, Mischel PS. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro-Oncology. 2010;12:882–9.PubMedCrossRef
11.
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.PubMedCrossRef
12.
Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US). Cited 2013 Feb 14.
13.
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.PubMedCrossRef
14.
Feng Z. p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol. 2010;2:a001057.PubMedCrossRef
15.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRef
16.
17.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.CrossRef
18.
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.PubMedCrossRef
19.
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.PubMedCrossRef
20.
21.
Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008;27:5416–30.PubMedCrossRef
22.
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.PubMedCrossRef
23.
Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol. 2003;4:117–26.PubMedCrossRef
24.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.PubMedCrossRef
25.
Dowling RJO, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 1804;2010:433–9.
26.
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.PubMedCrossRef
27.
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.PubMedCrossRef
28.
Volarević S, Thomas G. Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucleic Acid Res Mol Biol. 2001;65:101–27.PubMedCrossRef
29.
Sonenberg N, Gingras AC. The mRNA 5′ cap-binding protein eIF4E and control of cell growth. Curr Opin Cell Biol. 1998;10:268–75.PubMedCrossRef
30.
De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23:3189–99.PubMedCrossRef
31.
32.
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.PubMedCrossRef
33.
34.
Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320:1496–501.PubMedCrossRef
35.
36.
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.PubMedCrossRef
37.
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.PubMedCrossRef
38.
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.PubMedCrossRef
39.
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.PubMedCrossRef
40.
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.PubMedCrossRef
41.
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.PubMedCrossRef
42.
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.PubMedCrossRef
43.
Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134:451–60.PubMedCrossRef
44.
Knobbe CB, Merlo A, Reifenberger G. Pten signaling in gliomas. Neuro-Oncology. 2002;4:196–211.PubMed
45.
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.PubMedCrossRef
46.
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.PubMed
47.
Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H. PTEN methylation and expression in glioblastomas. Acta Neuropathol. 2003;106:479–85.PubMedCrossRef
48.
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.PubMedCrossRef
49.
Karsy M, Arslan E, Moy F. Current progress on understanding microRNAs in glioblastoma multiforme. Genes Cancer. 2012;3:3–15.PubMedCrossRef
50.
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.PubMedCrossRef
51.
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.PubMedCrossRef
52.
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.PubMed
53.
Downward J. Use of RNA interference libraries to investigate oncogenic signalling in mammalian cells. Oncogene. 2004;23:8376–83.PubMedCrossRef
54.
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.PubMed
55.
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.PubMed
56.
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.PubMed
57.
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.PubMedCrossRef
58.
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.PubMedCrossRef
59.
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.PubMedCrossRef
60.
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.PubMedCrossRef
61.
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.PubMedCrossRef
62.
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.PubMedCrossRef
63.
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.PubMedCrossRef
64.
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.PubMedCrossRef
65.
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.PubMedCrossRef
66.
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5:671–88.PubMedCrossRef
67.
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.PubMedCrossRef
68.
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.PubMedCrossRef
69.
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.PubMedCrossRef
70.
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.PubMedCrossRef
71.
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.PubMedCrossRef
72.
Molina JR, Hayashi Y, Stephens C, Georgescu M-M. Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia. 2010;12:453–63.PubMed
73.
Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle. 2009;8:3831–7.PubMedCrossRef
74.
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.PubMedCrossRef
75.
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.PubMedCrossRef
76.
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.PubMedCrossRef
77.
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.PubMedCrossRef
78.
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.PubMedCrossRef
79.
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.PubMedCrossRef
80.
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.PubMedCrossRef
81.
Cheng CK, Fan Q-W, Weiss WA. PI3K signaling in glioma—animal models and therapeutic challenges. Brain Pathol. 2009;19:112–20.PubMedCrossRef
82.
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.PubMedCrossRef
83.
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.PubMedCrossRef
84.
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.PubMedCrossRef
85.
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.PubMedCrossRef
86.
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.PubMedCrossRef
87.
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.PubMedCrossRef
88.
Fan Q-W, Weiss WA. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. Methods Mol Biol. 2012;821:349–59.PubMedCrossRef
89.
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.PubMedCrossRef
90.
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.PubMedCrossRef
91.
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.
92.
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.PubMedCrossRef
93.
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.PubMedCrossRef
94.
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.PubMed
95.
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.PubMed
96.
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.PubMedCrossRef
97.
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.PubMedCrossRef
98.
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.PubMedCrossRef
99.
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.PubMedCrossRef
100.
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.PubMedCrossRef
101.
McDowell KA, Riggins GJ, Gallia GL. Targeting the AKT pathway in glioblastoma. Curr Pharm Des. 2011;17:2411–20.PubMedCrossRef
102.
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.PubMedCrossRef
103.
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.PubMedCrossRef
104.
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.PubMedCrossRef
105.
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.
106.
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.PubMedCrossRef
107.
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.PubMed
108.
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.PubMedCrossRef
109.
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.PubMedCrossRef
110.
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.PubMedCrossRef
111.
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.PubMedCrossRef
112.
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.PubMedCrossRef
113.
Coppola JM, Ross BD, Rehemtulla A. Noninvasive imaging of apoptosis and its application in cancer therapeutics. Clin Cancer Res. 2008;14:2492–501.PubMedCrossRef
114.
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.PubMedCrossRef
115.
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.PubMedCrossRef
116.
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.PubMedCrossRef
117.
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.
118.
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.PubMedCrossRef
119.
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.PubMedCrossRef
120.
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.PubMedCrossRef
121.
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.PubMedCrossRef
122.
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.PubMedCrossRef
123.
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.PubMedCrossRef
124.
Metadata
Title
Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding
Authors
Arshawn Sami
Michael Karsy
Publication date
01-08-2013
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 4/2013
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-013-0800-5

Other articles of this Issue 4/2013

Tumor Biology 4/2013 Go to the issue

Research Article

CYP3A5*3 polymorphism and cancer risk: a meta-analysis and meta-regression

Research Article

Differential survival and recurrence patterns of patients operated for breast cancer according to the new immunohistochemical classification: analytical survey from 1997 to 2012

Research Article

Clinical and prognostic significance of Yes-associated protein in colorectal cancer

Research Article

Positive association between Toll-like receptor 4 gene +896A/G polymorphism and susceptibility to gastric carcinogenesis: a meta-analysis

Research Article

Apoptosis induction in human glioblastoma multiforme T98G cells upon temozolomide and quercetin treatment

Research Article

Extension of microRNA expression pattern associated with high-risk neuroblastoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits