PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression-free survival

Clinical Cancer Research

Volumn 19, Issue 23, 2013, Pages 6450-6460

  Rogers, Hazel A ^a   Mayne, Cerys ^a   Chapman, Rebecca J ^a   Kilday, John Paul ^a   Coyle, Beth ^a   Grundy, Richard G ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN D1; KI 67 ANTIGEN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOPROTEIN; PROTEIN KINASE B; TUMOR MARKER;

ARTICLE; BRAIN TUMOR; CELL PROLIFERATION; CHILD; DISEASE MARKER; DRUG TARGETING; ENZYME ACTIVATION; EPENDYMOMA; GENE; GENE EXPRESSION; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; MAJOR CLINICAL STUDY; PIK3CA GENE; PRESCHOOL CHILD; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; SPINAL CORD TUMOR; TUMOR LOCALIZATION;

BRAIN NEOPLASMS; CELL LINE, TUMOR; CELL PROLIFERATION; CHILD; CHILD, PRESCHOOL; CYCLIN D1; DISEASE-FREE SURVIVAL; EPENDYMOMA; FEMALE; HUMANS; KAPLAN-MEIER ESTIMATE; MALE; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASES; PROGNOSIS; PROTO-ONCOGENE PROTEINS C-AKT; PTEN PHOSPHOHYDROLASE; SIGNAL TRANSDUCTION; TRANSCRIPTOME; TUMOR MARKERS, BIOLOGICAL;

EID: 84890256881     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-13-0222     Document Type: Article

References (63)

1. Wright KD, Gajjar A. New chemotherapy strategies and biological agents in the treatment of childhood ependymoma. Childs Nerv Syst 2009;25:1275-82.
2. Zacharoulis S, Levy A, Chi SN, Gardner S, Rosenblum M, Miller DC, et al. Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer 2007;49:34-40.
3. Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 2009;10:258-66.
4. Duffner PK, Krischer JP, Sanford RA, Horowitz ME, Burger PC, Cohen ME, et al. Prognostic factors in infants and very young children with intracranial ependymomas. Pediatr Neurosurg 1998;28:215-22.
5. Amirian ES, Armstrong TS, Aldape KD, Gilbert MR, Scheurer ME. Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007. Neuroepidemiology 2012;39:116-24.
6. McGuire CS, Sainani KL, Fisher PG. Both location and age predict survival in ependymoma: a SEER study. Pediatr Blood Cancer 2009;52:65-9.
7. Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 2010;466:632-6.
8. Rogers HA, Kilday JP, Mayne C, Ward J, Adamowicz-Brice M, Schwalbe EC, et al. Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death. Acta Neuropathol 2012;123:711-25.
9. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005;8:323-35.
10. Kilday JP, Rahman R, Dyer S, Ridley L, Lowe J, Coyle B, et al. Pediatric ependymoma: biological perspectives. Mol Cancer Res 2009;7:765-86.
11. Tihan T, Zhou T, Holmes E, Burger PC, Ozuysal S, Rushing EJ. The prognostic value of histological grading of posterior fossa ependymomas in children: a Children's Oncology Group study and a review of prognostic factors. Mod Pathol 2008;21:165-77.
12. Horn B, Heideman R, Geyer R, Pollack I, Packer R, Goldwein J, et al. A multi-institutional retrospective study of intracranial ependymoma in children: identification of risk factors. J Pediatr Hematol Oncol 1999;21:203-11.
13. Sowar K, Straessle J, Donson AM, Handler M, Foreman NK. Predicting which children are at risk for ependymoma relapse. J Neurooncol 2006;78:41-6.
14. Ridley L, Rahman R, Brundler MA, Ellison D, Lowe J, Robson K, et al. Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro Oncol 2008;10:675-89.
15. Bennetto L, Foreman N, Harding B, Hayward R, Ironside J, Love S, et al. Ki-67 immunolabelling index is a prognostic indicator in childhood posterior fossa ependymomas. Neuropathol Appl Neurobiol 1998;24:434-40.
16. Kilday JP, Mitra B, Domerg C, Ward J, Andreiuolo F, Osteso-Ibanez T, et al. Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children's Cancer Leukaemia Group (CCLG), Societe Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP). Clin Cancer Res 2012;18:2001-11.
17. Milde T, Hielscher T, Witt H, Kool M, Mack SC, Deubzer HE, et al. Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol 2012;22:848-60.
18. Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011;20:143-57.
19. Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, et al. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol 2004;22:1926-33.
20. Hartmann W, Digon-Sontgerath B, Koch A, Waha A, Endl E, Dani I, et al. Phosphatidylinositol 30-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res 2006;12:3019-27.
21. Vogt PK, Bader AG, Kang S. Phosphoinositide 3-kinase: from viral oncoprotein to drug target. Virology 2006;344:131-8.
22. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627-44.
23. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061-8.
24. 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.
25. Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet 2007;39:347-51.
26. Grundy RG, Wilne SA, Weston CL, Robinson K, Lashford LS, Ironside J, et al. Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study. Lancet Oncol 2007;8:696-705.
27. Grundy R, Jaspan T, Macarthur D, Wilne S, Kilday JP, Mallucci C, et al. Outcome of children treated for intracranial ependymoma: the first SIOP trial. Pediatr Blood Cancer 2012;59:992.
28. Benjamini Y, Hochberg Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J R Stat Soc B 1995;57:289-300.
29. Pfaffi MW. A new mathematical model for relative quantification in realtime RT-PCR. Nucleic Acids Res 2001;29:e45.
30. Rogers HA, Miller S, Lowe J, Brundler MA, Coyle B, Grundy RG. An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumours (CNS PNET). Br J Cancer 2009;100:1292-302.
31. Yu L, Baxter PA, Voicu H, Gurusiddappa S, Zhao Y, Adesina A, et al. A clinically relevant orthotopic xenograft model of ependymoma that maintains the genomic signature of the primary tumor and preserves cancer stem cells in vivo. Neuro Oncol 2010;12:580-94.
32. Hussein D, Punjaruk W, Storer LC, Shaw L, Othman R, Peet A, et al. Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion. Neuro Oncol 2011;13:70-83.
33. Bobola MS, Silber JR, Ellenbogen RG, Geyer JR, Blank A, Goff RD. O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines. Clin Cancer Res 2005;11:2747-55.
34. Levesley J, Lusher ME, Lindsey JC, Clifford SC, Grundy R, Coyle B. RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines. Neuro Oncol 2011;13:1265-76.
35. Atkinson JM, Shelat AA, Carcaboso AM, Kranenburg TA, Arnold LA, Boulos N, et al. An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell 2011;20:384-99.
36. Wen PY, Lee EQ, Reardon DA, Ligon KL, Alfred Yung WK. Current clinical development of PI3K pathway inhibitors in glioblastoma. Neuro Oncol 2012;14:819-29.
37. Koul D, Fu J, Shen R, La Fortune 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.
38. Bendell JC, Rodon J, Burris HA, De Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 2012;30:282-90.
39. Capodanno A, Camerini A, Orlandini C, Baldini E, Resta ML, Bevilacqua G, et al. Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Hum Pathol 2009;40:1408-17.
40. Pejavar S, Polley MY, Rosenberg-Wohl S, Chennupati S, Prados MD, Berger MS, et al. Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. J Neurooncol 2012;106:367-75.
41. Perilongo G, Massimino M, Sotti G, Belfontali T, Masiero L, Rigobello L, et al. Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group. Med Pediatr Oncol 1997;29:79-85.
42. Sala F, Talacchi A, Mazza C, Prisco R, Ghimenton C, Bricolo A. Prognostic factors in childhood intracranial ependymomas: the role of age and tumor location. Pediatr Neurosurg 1998;28:135-42.
43. Vaidya K, Smee R, Williams JR. Prognostic factors and treatment options for paediatric ependymomas. J Clin Neurosci 2012;19:1228-35.
44. Saji M, Ringel MD. The PI3K-Akt-mTOR pathway in initiation and progression of thyroid tumors. Mol Cell Endocrinol 2010;321:20-8.
45. Saji M, Vasko V, Kada F, Allbritton EH, Burman KD, Ringel MD. Akt1 contains a functional leucine-rich nuclear export sequence. Biochem Biophys Res Commun 2005;332:167-73.
46. Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandol. PP. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 2006;441:523-7.
47. Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A 1998;95:15406-11.
48. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-19.
49. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998;12:3499-511.
50. Prayson RA. Cyclin D1 and MIB-1 immunohistochemistry in ependymomas: a study of 41 cases. Am J Clin Pathol 1998;110:629-34.
51. Zawrocki A, Izycka-Swieszewska E, Papierz W, Liberski PP, Zakrzewski K, Biernat W. Analysis of the prognostic significance of selected morphological and immunohistochemical markers in ependymomas, with literature review. Folia Neuropathol 2011;49:94-102.
52. Zamecnik J, Snuderl M, Eckschlager T, Chanova M, Hladikova M, Tichy M, et al. Pediatric intracranial ependymomas: prognostic relevance of histological, immunohistochemical, and flow cytometric factors. Mod Pathol 2003;16:980-91.
53. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007;12:104-7.
54. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-44.
55. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 1998;21:81-6.
56. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci U S A 1987;84:5034-7.
57. Nazarenko I, Hede SM, He X, Hedren A, Thompson J, Lindstrom MS, et al. PDGF and PDGF receptors in glioma. Ups J Med Sci 2012;117:99-112.
58. Gilbertson RJ, Bentley L, Hernan R, Junttila TT, Frank AJ, Haapasalo H, et al. ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease. Clin Cancer Res 2002;8:3054-64.
59. Mendrzyk F, Korshunov A, Benner A, Toedt G, Pster S, Radlwimmer B, et al. Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 2006;12:2070-9.
60. Moreno L, Popov S, Jury A, Al Sarraj S, Jones C, Zacharoulis S. Role of platelet derived growth factor receptor (PDGFR) over-expression and angiogenesis in ependymoma. J Neurooncol 2013;111:169-76.
61. Modena P, Buttarelli FR, Miceli R, Piccinin E, Baldi C, Antonelli M, et al. Predictors of outcomein an AIEOP series of childhood ependymomas: a multifactorial analysis. Neuro Oncol 2012;14:1346-56.
62. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-93.
63. Wander SA, Hennessy BT, Slingerland JM. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest 2011;121:1231-41.