Abstract
Gliomas represent the most common primary brain tumor and among the most aggressive of cancers. Patients with glioma typically relapse within a year of initial diagnosis. Recurrent glioma is associated with acquired therapeutic resistance. Although neurosurgical resection, radiation and chemotherapy provide clear benefit, survival remains disappointing. It is, therefore, critical that we identify effective medical therapies and appropriate tumor biomarkers in patients at initial presentation, to promote durable responses in glioma. Pathways linking receptor tyrosine kinases, PI3 kinase, Akt, and mTOR feature prominently in this disease and represent therapeutic targets. Small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity. Disappointingly, however, preclinical studies demonstrate these agents to be primarily cytostatic rather than cytotoxic to glioma cells. Here, we detail activation of the EGFR-PI3K-Akt-mTOR signaling network in glioma, review class I PI3K inhibitors, discuss roles for Akt, PKC and mTOR, and the importance of biomarkers. We further delineate attempts to target both single and multiple components within the EGFR-PI3K-Akt-mTOR axes. Lastly, we discuss the need to combine targeted therapies with cytotoxic chemotherapy, radiation and with inhibitors of survival signaling to improve outcomes in glioma.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- CML:
-
Chronic myelongenous leukemia
- EGFR:
-
Epidermal growth factor receptor
- GBM:
-
Glioblastoma multiforme
- mTOR:
-
Mammalian target of rapamycin
- PKC:
-
Protein kinase C
- PI3K:
-
Phosphatidylinositol 3′kinase
- RTK:
-
Receptor tyrosine kinase
References
Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R (2008) Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res 14:957–960
Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068
Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J et al (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361
Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight ZA, Weiss W, Shokat KM, Haas-Kogan D, Stokoe D (2008) Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7:841–850
Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma–animal models and therapeutic challenges. Brain Pathol 19:112–120
Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H et al (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 1:ra3
Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D et al (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5:e8
Copp J, Manning G, Hunter T (2009) TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69:1821–1827
de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, Groves MD, Conrad C, Colman H, Puduvalli VK et al (2008) Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol 90:89–97
Degtyarev M, De Maziere A, Orr C, Lin J, Lee BB, Tien JY, Prior WW, van Dijk S, Wu H, Gray DC et al (2008) Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J Cell Biol 183:101–116
Doherty L, Gigas DC, Kesari S, Drappatz J, Kim R, Zimmerman J, Ostrowsky L, Wen PY (2006) Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 67:156–158
Fan QW, Specht KM, Zhang C, Goldenberg DD, Shokat KM, Weiss WA (2003) Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach. Cancer Res 63:8930–8938
Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9:341–349
Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, Weiss WA (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67:7960–7965
Fan QW, Cheng C, Knight ZA, Haas-Kogan D, Stokoe D, James CD, McCormick F, Shokat KM, Weiss WA (2009) EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal 2:ra4
Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2. PLoS Biol 7:e38
Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D, Scopece L, Blatt V, Urbini B, Pession A et al (2007) Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer 96:1047–1051
Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304
Graff JR, McNulty AM, Hanna KR, Konicek BW, Lynch RL, Bailey SN, Banks C, Capen A, Goode R, Lewis JE et al (2005) The protein kinase Cbeta-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462–7469
Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, Baumber R, Lamborn KR, Kapadia A, Malec M et al (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y et al (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 11:507–514
Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806
Kao GD, Jiang Z, Fernandes AM, Gupta AK, Maity A (2007) Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 282:21206–21212
Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733–747
Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9:1004–1010
Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K et al (2008) 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 7:1851–1863
Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD et al (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031–1034
Opel D, Westhoff MA, Bender A, Braun V, Debatin KM, Fulda S (2008) Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res 68:6271–6280
Persson A, Fan Q-W, Phillips J, Weiss WA (2007) Glioma. Elsevier, San Diego
Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A et al (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol 8:67–78
Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M et al (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584
Prevo R, Deutsch E, Sampson O, Diplexcito J, Cengel K, Harper J, O'Neill P, McKenna WG, Patel S, Bernhard EJ (2008) Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 68:5915–5923
Reardon DA, Quinn JA, Vredenburgh JJ, Gururangan S, Friedman AH, Desjardins A, Sathornsumetee S, Herndon JE II, Dowell JM, McLendon RE et al (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868
Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142
Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I et al (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040–1046
Sawyers C (2004) Targeted cancer therapy. Nature 432:294–297
Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C et al (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996
Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mTOR inhibitor reveals rapamycin-insensitive functions of mTORC1. J Biol Chem 284:8023–8032
Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 66:7864–7869
Acknowledgments
We are grateful to Kevan Shokat for useful discussions and to Theo Nicolaides for critical review. We acknowledge support from NIH P50CA097257, Burroughs Wellcome Fund, American Brain Tumor Association, The Brain Tumor Society, Accelerate Brain Cancer Cure; Alex’s Lemonade Stand, Children’s National Brain Tumor, Wallace H. Coulter, Katie Dougherty, Pediatric Brain Tumor, Samuel G. Waxman and V Foundations.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Fan, QW., Weiss, W.A. (2010). Targeting the RTK-PI3K-mTOR Axis in Malignant Glioma: Overcoming Resistance. In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 347. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_67
Download citation
DOI: https://doi.org/10.1007/82_2010_67
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-14815-6
Online ISBN: 978-3-642-14816-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)