PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.

[1]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[2]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[3]  T. Cloughesy,et al.  Emerging function of mTORC2 as a core regulator in glioblastoma: metabolic reprogramming and drug resistance , 2014, Cancer biology & medicine.

[4]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[5]  Alona Muzikansky,et al.  The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  H. Ng,et al.  Effects of cotransfection of antisense‐EGFR and wild‐type PTEN cDNA on human glioblastoma cells , 2006, Neuropathology : official journal of the Japanese Society of Neuropathology.

[7]  Paul Workman,et al.  Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. , 2008, Current opinion in pharmacology.

[8]  Li Zhao,et al.  Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms , 2008, Proceedings of the National Academy of Sciences.

[9]  Alessia Pica,et al.  Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  K. Debatin,et al.  A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy , 2014, Molecular and Cellular Therapies.

[11]  W. Yung,et al.  NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas , 2009, Molecular Cancer Therapeutics.

[12]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[13]  Jayson A. Neil,et al.  Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: a tale of two complexes. , 2015, Advances in biological regulation.

[14]  R. McLendon,et al.  Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. , 2010, Neuro-oncology.

[15]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. , 2013, Neuro-oncology.

[16]  O. Delattre,et al.  Targeting the PI3K p110α Isoform Inhibits Medulloblastoma Proliferation, Chemoresistance, and Migration , 2008, Clinical Cancer Research.

[17]  K Y Hui,et al.  A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). , 1994, The Journal of biological chemistry.

[18]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[19]  J. Tabernero,et al.  Targeting the PI3K/Akt/mTOR Pathway – Beyond Rapalogs , 2010, Oncotarget.

[20]  A. Unterberg,et al.  Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. , 2006, Cancer treatment reviews.

[21]  N. Hay Interplay between FOXO, TOR, and Akt. , 2011, Biochimica et biophysica acta.

[22]  P. Richardson,et al.  Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenström's Macroglobulinemia , 2010, Clinical Cancer Research.

[23]  H. Gach,et al.  Akt signaling is required for glioblastoma maintenance in vivo. , 2011, American journal of cancer research.

[24]  D. Guertin,et al.  Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex , 2005, Science.

[25]  K. Aldape,et al.  Using the molecular classification of glioblastoma to inform personalized treatment , 2014, The Journal of pathology.

[26]  William A Weiss,et al.  Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORC1/2 inhibitors. , 2012, Methods in molecular biology.

[27]  P. Mischel,et al.  mTORC2 in the center of cancer metabolic reprogramming , 2014, Trends in Endocrinology & Metabolism.

[28]  M. Pincus,et al.  Novel mutations of epidermal growth factor receptor in localized prostate cancer. , 2006, Frontiers in bioscience : a journal and virtual library.

[29]  E. Holland,et al.  Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo. , 2005, Cancer research.

[30]  J. Hainsworth,et al.  Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma. , 2012, Clinical advances in hematology & oncology : H&O.

[31]  G. Reifenberger,et al.  Genetic alteration and expression of the phosphoinositol‐3‐kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas , 2005, Neuropathology and applied neurobiology.

[32]  M. Delorenzi,et al.  Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial , 2011, Molecular Cancer Therapeutics.

[33]  C. Kang,et al.  Increased expression of Akt2 and activity of PI3K and cell proliferation with the ascending of tumor grade of human gliomas , 2010, Clinical Neurology and Neurosurgery.

[34]  A. Sami,et al.  Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding , 2013, Tumor Biology.

[35]  W. Yung,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 , 2011, Clinical Cancer Research.

[36]  David M Sabatini,et al.  An expanding role for mTOR in cancer. , 2005, Trends in molecular medicine.

[37]  P. Wipf,et al.  Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. , 2004, Molecular cancer therapeutics.

[38]  S. Toms,et al.  Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme , 2010, Journal of Neuro-Oncology.

[39]  The Cancer Genome Atlas Research Network Corrigendum: Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2013, Nature.

[40]  C. Beaudry,et al.  Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis , 2003, Journal of Cell Science.

[41]  Daniela Gabriel,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 , 2008, Molecular Cancer Therapeutics.

[42]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[43]  K. Shokat,et al.  Chemically targeting the PI3K family. , 2007, Biochemical Society transactions.

[44]  S. Weiss,et al.  Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival , 2014, Clinical Cancer Research.

[45]  Adam Dicker,et al.  The contribution of epidermal growth factor receptor (EGFR) signaling pathway to radioresistance in human gliomas: a review of preclinical and correlative clinical data. , 2004, International journal of radiation oncology, biology, physics.

[46]  Q. Gao,et al.  Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma , 2013, Expert opinion on investigational drugs.

[47]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[48]  Susan M. Chang,et al.  Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. , 2014, Neuro-oncology.

[49]  A. Clavreul,et al.  Toward an effective strategy in glioblastoma treatment. Part II: RNA interference as a promising way to sensitize glioblastomas to temozolomide. , 2015, Drug discovery today.

[50]  Lisa L. Smith,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. , 2010, Cancer research.

[51]  R. Copeland,et al.  Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. , 2008, The Biochemical journal.

[52]  Nahum Sonenberg,et al.  Dissecting the role of mTOR: lessons from mTOR inhibitors. , 2010, Biochimica et biophysica acta.

[53]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[54]  A. Degterev,et al.  Role of phosphatidylinositol 3,4,5-trisphosphate in cell signaling. , 2013, Advances in experimental medicine and biology.

[55]  P. Furet,et al.  Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. , 2008, Bioorganic & medicinal chemistry letters.

[56]  W. Mason,et al.  Phase II study of PX-866 in recurrent glioblastoma. , 2012, Neuro-oncology.

[57]  W. Yung,et al.  Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. , 2010, Neuro-oncology.

[58]  J. Dodge,et al.  Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. , 1994, Cancer research.

[59]  Debyani Chakravarty,et al.  Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response , 2012, Proceedings of the National Academy of Sciences.

[60]  S. Horvath,et al.  Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma , 2008, PLoS medicine.

[61]  P. Vogt,et al.  Cancer-specific mutations in PIK3CA are oncogenic in vivo , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[62]  M. Karsy,et al.  Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility. , 2009, International journal of oncology.

[63]  Forest M White,et al.  Oncogenic EGFR Signaling Networks in Glioma , 2009, Science Signaling.

[64]  Jordi Rodon,et al.  Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  M. J. van den Bent,et al.  Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  T. Cloughesy,et al.  Glioblastoma: from molecular pathology to targeted treatment. , 2014, Annual review of pathology.

[67]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[68]  W. Cavenee,et al.  A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[69]  T. Cloughesy,et al.  Targeted therapy for malignant glioma patients: Lessons learned and the road ahead , 2009, Neurotherapeutics.

[70]  G. Powis,et al.  Advances with phospholipid signalling as a target for anticancer drug development. , 1995, Acta biochimica Polonica.

[71]  I. Kim,et al.  Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases , 2014, BMC Cancer.

[72]  J. Dry,et al.  Benefits of mTOR kinase targeting in oncology: pre-clinical evidence with AZD8055. , 2011, Biochemical Society transactions.

[73]  M. Berger,et al.  Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. , 2005, Journal of the National Cancer Institute.

[74]  William A Weiss,et al.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. , 2006, Cancer cell.

[75]  Y. Hu,et al.  PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion , 2007, Oncogene.

[76]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[77]  J. Dixon,et al.  PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy* , 2002, The Journal of Biological Chemistry.

[78]  P. Wen,et al.  Current clinical development of PI3K pathway inhibitors in glioblastoma. , 2012, Neuro-oncology.

[79]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.

[80]  R. Copeland,et al.  Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase , 2008 .

[81]  Caterina Giannini,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. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[83]  H. Wakimoto,et al.  A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models. , 2011, Cancer research.

[84]  H. Burris,et al.  Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway , 2013, Cancer Chemotherapy and Pharmacology.

[85]  Carlo Rago,et al.  Mutant PIK3CA promotes cell growth and invasion of human cancer cells. , 2005, Cancer cell.

[86]  Qiang Wang,et al.  ErbB receptors: from oncogenes to targeted cancer therapies. , 2007, The Journal of clinical investigation.

[87]  I. Ben-Sahra,et al.  Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. , 2011, Cancer research.

[88]  R. McLendon,et al.  Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma , 2009, Journal of Neuro-Oncology.

[89]  J. Engelman,et al.  The PI3K pathway as drug target in human cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[91]  Susan M. Chang,et al.  Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme , 2005, Investigational New Drugs.

[92]  O. Wiestler,et al.  Phosphatidylinositol 3′-Kinase/AKT Signaling Is Activated in Medulloblastoma Cell Proliferation and Is Associated with Reduced Expression of PTEN , 2006, Clinical Cancer Research.

[93]  David M Sabatini,et al.  Defining the role of mTOR in cancer. , 2007, Cancer cell.