Journal of Neuro-Oncology

, Volume 99, Issue 2, pp 155–163 | Cite as

Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children’s Oncology Group

  • Ian F. Pollack
  • Ronald L. Hamilton
  • Peter C. Burger
  • Daniel J. Brat
  • Marc K. Rosenblum
  • Geoffrey H. Murdoch
  • Marina N. Nikiforova
  • Emiko J. Holmes
  • Tianni Zhou
  • Kenneth J. Cohen
  • Regina I. Jakacki
  • The Children’s Oncology Group
Priority Report


Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising in adults, have a substantially lower incidence of genomic alterations of PTEN. The objective of this study was to determine whether Akt activation was also an uncommon finding in childhood malignant gliomas and whether this feature was associated with survival. To address this issue, we examined the frequency of Akt activation, determined by overexpression of the activated phosphorylated form of Akt (Se473) on immunohistochemical analysis, in a series of 53 childhood malignant gliomas obtained from newly diagnosed patients treated on the Children’s Oncology Group ACNS0126 and 0423 studies. The relationship between Akt activation and p53 overexpression, MIB1 labeling, and tumor histology was evaluated. The association between Akt activation and survival was also assessed. Overexpression of activated Akt was observed in 42 of 53 tumors, far in excess of the frequency of PTEN mutations we have previously observed. There was no association between Akt activation and either histology, p53 overexpression, or MIB1 proliferation indices. Although tumors that lacked Akt overexpression had a trend toward more favorable event-free survival and overall survival (p = 0.06), this association reflected that non-overexpressing tumors were significantly more likely to have undergone extensive tumor removal, which was independently associated with outcome. Activation of Akt is a common finding in pediatric malignant gliomas, although it remains uncertain whether this is an independent adverse prognostic factor. In view of the frequency of Akt activation, the evaluation of molecularly targeted therapies that inhibit this pathway warrants consideration for these tumors.


Anaplastic glioma Childhood Glioblastoma Akt Prognostic factors Treatment resistance 



This work was supported in part by NIH grants NS37704 (IFP), and CA98543 to the Children’s Oncology Group. The authors wish to acknowledge Judith Burnham for technical assistance.


  1. 1.
    Pollack IF (1994) Current concepts: brain tumors in children. N Engl J Med 331:1500–1507CrossRefPubMedGoogle Scholar
  2. 2.
    Pollack IF, Hamilton RL, James CD, Finkelstein SD, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children’s Cancer Group 945 cohort. J Neurosurg Pediatr 105:3431–3437CrossRefGoogle Scholar
  3. 3.
    Sung T, Miller DC, Hayes RL, Alonso M, Yee H, Newcomb EW (2000) Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol 10:249–259CrossRefPubMedGoogle Scholar
  4. 4.
    Bredel M, Pollack IF, Hamilton RL, James CD (1999) Epidermal growth factor receptor (EGFR) expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res 5:1786–1792PubMedGoogle Scholar
  5. 5.
    Cheng Y, Ng H-K, Zhang S-F, Ding M, Pang JC-S, Zheng J, Poon W-S (1999) Genetic alterations in pediatric high-grade astrocytomas. Hum Pathol 30:1284–1290CrossRefPubMedGoogle Scholar
  6. 6.
    Raffel C, Frederick L, O’Fallon JR et al (1999) Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. Clin Cancer Res 5:4085–4090PubMedGoogle Scholar
  7. 7.
    Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Boyett JM, Finlay JL, Sposto R (2002) Expression of p53 and prognosis in malignant gliomas in children. N Engl J Med 346:420–427CrossRefPubMedGoogle Scholar
  8. 8.
    Thorarinsdottir HK, Santi M, McCarter R, Rushing EJ, Cornelison R, Jales A, MacDonald TJ (2008) Protein expression of platelet-derived growth factor receptor correlates with malignant histology and PTEN with survival in childhood gliomas. Clin Cancer Res 14:3386–3394CrossRefPubMedGoogle Scholar
  9. 9.
    Liang M-L, Ma J, Ho M et al (2008) Tyrosine kinase expression in pediatric high grade astrocytoma. J Neurooncol 87:247–253CrossRefPubMedGoogle Scholar
  10. 10.
    Sure U, Ruedi D, Tachibana O et al (1997) Determination of p53 mutations, EGFR overexpression, and loss of p16 expression in pediatric glioblastomas. J Neuropathol Exp Neurol 56:782–789PubMedGoogle Scholar
  11. 11.
    Pollack IF, Finkelstein SD, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Finlay J, Sposto R (2001) Age and TP53 mutation frequency in childhood malignant gliomas. Results in a multi-institutional cohort. Cancer Res 61:7404–7407PubMedGoogle Scholar
  12. 12.
    Collins VP (1999) Progression as exemplified by human astrocytic tumors. Semin Cancer Biol 9:267–276CrossRefPubMedGoogle Scholar
  13. 13.
    Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP (2000) Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60:417–424PubMedGoogle Scholar
  14. 14.
    von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN (1993) Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26CrossRefGoogle Scholar
  15. 15.
    Watanabe K, Tachibana O, Sato K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–224CrossRefPubMedGoogle Scholar
  16. 16.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812CrossRefPubMedGoogle Scholar
  17. 17.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947CrossRefPubMedGoogle Scholar
  18. 18.
    Faury D, Nantel A, Dunn SE, Guiot M-C, Haque T, Hauser P, Garami M, Bognar L, Hanzély Z, Liberski PP, Lopez-Aguilar E, Valera ET, Tone LG, Carret A-S, Del Maestro RF, Gleave M, Montes J-L, Pietsch T, Albrecht S, Jabado N (2007) Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol 25:1196–1208CrossRefPubMedGoogle Scholar
  19. 19.
    Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789CrossRefPubMedGoogle Scholar
  20. 20.
    Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321CrossRefPubMedGoogle Scholar
  21. 21.
    Rhodes N, Heerding DA, Duckett DR et al (2008) Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 68:2366–2374CrossRefPubMedGoogle Scholar
  22. 22.
    Prevo R, Deutsch E, Sampson O et al (2008) Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 68:5915–5923CrossRefPubMedGoogle Scholar
  23. 23.
    Garlich JR, De P, Dey N et al (2008) A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 68:206–215CrossRefPubMedGoogle Scholar
  24. 24.
    Fan Q-W, Cheng CK, Nicolaides TP et al (2007) A dual phosphoinositide-3-kinase α/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN–mutant glioma. Cancer Res 67:7960–7965CrossRefPubMedGoogle Scholar
  25. 25.
    Serra V, Markman B, Scaltriti M et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3 K signaling and inhibits growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022–8030CrossRefPubMedGoogle Scholar
  26. 26.
    Thaker NG, Pollack IF (2009) Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies. Expert Rev Neurother 9:1815–1836CrossRefPubMedGoogle Scholar
  27. 27.
    Ihle NT, Powis G (2009) Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 8:1–9CrossRefPubMedGoogle Scholar
  28. 28.
    Liu T-J, Koul D, LaFortune T et al (2009) NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 8:2204–2210CrossRefPubMedGoogle Scholar
  29. 29.
    Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304CrossRefPubMedGoogle Scholar
  30. 30.
    Doherty L, Gigas DC, Kesari S et al (2006) Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 67:156–158CrossRefPubMedGoogle Scholar
  31. 31.
    Reardon DA, Quinn JA, Vredenburgh JJ et al (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868CrossRefPubMedGoogle Scholar
  32. 32.
    Wang MY, Lu KV, Zhu S et al (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 66:7864–7869CrossRefPubMedGoogle Scholar
  33. 33.
    Shi SR, Key ME, Kalra KL (1991) Antigen retrieval in formalin-fixed, paraffin embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem 39:741–748PubMedGoogle Scholar
  34. 34.
    Vojtesek B, Bartek J, Midgley CA, Lane DP (1992) An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. J Immunol Methods 151:237–244CrossRefPubMedGoogle Scholar
  35. 35.
    Hsu S, Raine L, Fanger H et al (1981) Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques. J Histochem Cytochem 29:577–580PubMedGoogle Scholar
  36. 36.
    Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, Kreisberg JI (2002) Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 8:1168–1171PubMedGoogle Scholar
  37. 37.
    Schlieman MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ (2003) Incidence, mechanism and prognostic value of activated Akt in pancreas cancer. Molec Cell Pathol 89:2110–2115Google Scholar
  38. 38.
    Pollack IF, Hamilton RL, Burnham J, Holmes EJ, Finkelstein SD, Sposto R, Yates AJ, Boyett JM, Finlay JL (2002) Impact of proliferation index on outcome in childhood malignant gliomas: results in a multi-institutional cohort. Neurosurgery 50:1238–1244CrossRefPubMedGoogle Scholar
  39. 39.
    Pollack IF, Boyett JM, Yates AJ, Burger PC, Gilles FH, Davis RL, Finlay JL (2003) The influence of central review on outcome associations in childhood malignant gliomas: Results from the CCG-945 experience. Neuro Oncol 5:197–207CrossRefPubMedGoogle Scholar
  40. 40.
    Kalbfleisch JD, Prentice RI (1980) The statistical analysis of failure time data. Wiley, New York, pp 163–180Google Scholar
  41. 41.
    Dixon WJ, Massey FJ (1969) Introduction to statistical analysis, 3rd edn. McGraw-Hill, New YorkGoogle Scholar
  42. 42.
    Perez-Tenorio G, Stal O (2002) Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 86:540–545CrossRefPubMedGoogle Scholar
  43. 43.
    Gupta AK, McKenna WG, Weber CN, Feldman MD, Goldsmith JD, Mick R, Machtay M, Rosenthal DI, Bakanauskas VJ, Cerniglia GJ, Bernhard EJ, Weber RS, Muschel RJ (2002) Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res 8:885–892PubMedGoogle Scholar
  44. 44.
    Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JKV, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554CrossRefPubMedGoogle Scholar
  45. 45.
    Gallia GL, Rand V, Siu I-M, Eberhart CG, James CD, Marie SKN, Oba-Shinjo SM, Carlotti CG, Caballero OL, Simpson AJG, Brock MV, Massion PP, Carson BS Jr, Riggins GJ (2006) PI3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4:709–713CrossRefPubMedGoogle Scholar
  46. 46.
    Wiencke JK, Zheng S, Jelluma N, Tihan T, Vandenberg S, Tamgüney T, Baumber R, Parsons R, Lamborn KR, Berger MS, Wrensch MR, Haas-Kogan DA, Stokoe D (2007) Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol 9:271–279CrossRefPubMedGoogle Scholar
  47. 47.
    Chadha KS, Khoury T, Yu J et al (2006) Activated Akt and Erk expression and survival after surgery in pancreatic carcinoma. Ann Surg Oncol 13:933–939CrossRefPubMedGoogle Scholar
  48. 48.
    Petricoin EF III, Espina V, Araujo RP et al (2007) Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res 67:3431–3440CrossRefPubMedGoogle Scholar
  49. 49.
    Opel D, Poremba C, Simon T, Debatin K-M, Fulda S (2007) Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res 67:735–745CrossRefPubMedGoogle Scholar
  50. 50.
    Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, Ghosh PM (2004) Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res 64:5232–5236CrossRefPubMedGoogle Scholar
  51. 51.
    Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB (2001) PTEN mutation, EGFR amplication, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256CrossRefPubMedGoogle Scholar
  52. 52.
    Gera JF, Mellinghoff IK, Shi Y, Rettig MB, Tran C, Hsu JH, Sawyers CL, Lichtenstein AK (2004) AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 279:2737–2746CrossRefPubMedGoogle Scholar
  53. 53.
    Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong J, Mills GB, Hung MC, Meric-Bernstam F (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 10:1013–1023CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Ian F. Pollack
    • 1
  • Ronald L. Hamilton
    • 2
  • Peter C. Burger
    • 4
  • Daniel J. Brat
    • 6
  • Marc K. Rosenblum
    • 7
  • Geoffrey H. Murdoch
    • 2
  • Marina N. Nikiforova
    • 2
  • Emiko J. Holmes
    • 8
  • Tianni Zhou
    • 8
  • Kenneth J. Cohen
    • 5
  • Regina I. Jakacki
    • 3
  • The Children’s Oncology Group
  1. 1.Department of Neurosurgery, Children’s Hospital of PittsburghUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of PediatricsUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  5. 5.Department of OncologyJohns Hopkins UniversityBaltimoreUSA
  6. 6.Department of PathologyEmory UniversityAtlantaUSA
  7. 7.Department of PathologyMemorial Sloan-Kettering Cancer CenterNewyorkUSA
  8. 8.The Children’s Oncology GroupArcadiaUSA

Personalised recommendations