Oncologie

, Volume 11, Issue 2, pp 67–71 | Cite as

Glioblastomes: aspects moléculaires et prise en charge actuelle

Synthèse / Review Article
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Résumé

Les glioblastomes (GB) sont les gliomes les plus fréquents et les plus graves de l’adulte. Au plan moléculaire, ils se caractérisent par une activation de la voie des récepteurs tyrosine-kinase (RTK) aux facteurs de croissance et par une inhibition de la voie des gènes suppresseurs de tumeurs p53 et RB1. L’état de méthylation du gène de la MGMT est le facteur pronostique moléculaire le plus important et semble prédire la chimiosensibilité aux alkylants. Comme dans d’autres cancers, des cellules souches cancéreuses ont été identifiées et pourraient constituer une cible thérapeutique privilégiée. La prise en charge des GB repose actuellement sur la chirurgie, la radiothérapie et la chimiothérapie. La radiochimiothérapie concomitante (RTCT), selon le protocole de Stupp applicable à la majorité des patients atteints de GB, constitue le progrès thérapeutique récent le plus important. La place de la chimiothérapie dans les formes inopérables et chez les sujets âgés reste à préciser. L’impact des thérapies ciblées en première ligne de traitement constitue un enjeu majeur des essais en développement.

Mots clés

Glioblastome Chimiothérapie MGMT Cellule souche cancéreuse 

Glioblastomas: molecular aspects and current management

Abstract

Glioblastomas are the kind of malignant gliomas found most frequently in adults. In nearly all glioblastomas there is activation of the receptor tyrosine-kinase pathway and deactivation of the p53 and retinoblastoma tumor suppressor pathways. The methylation status of the MGMT gene promoter is the most importantmolecular prognostic factor and may predict chemosensitivity to alkylating agents. As in other cancers, cancer stem cells have been identified in glioblastomas, where they could be important therapeutic target. Management of glioblastomas involves surgery, radiotherapy and chemotherapy. Concomitant chemoradiotherapy according to Stupp’s regimen is the most important recent therapeutic advance. However, the benefit of chemotherapy for inoperable tumors or in the elderly population remains to be determined. The impact of targeted therapies as part of first line treatment is under evaluation.

Keywords

Glioblastoma Chemotherapy MGMT Cancer stem cell 

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Références

  1. 1.
    Asthagiri AR, Pouratian N, Sherman J, et al. (2007) Advances in brain tumor surgery. Neurol Clin 25: 975–1003, viii–ixPubMedCrossRefGoogle Scholar
  2. 2.
    Bao S, Wu Q, Li Z, et al. (2008) Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 68: 6043–6048PubMedCrossRefGoogle Scholar
  3. 3.
    Bao S, Wu Q, McLendon RE, et al. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760PubMedCrossRefGoogle Scholar
  4. 4.
    Bauchet L, Rigau V, Mathieu-Daudé H, et al. (2007) French brain tumor data bank: methodology and first results on 10,000 cases. J Neurooncol 84: 189–199PubMedCrossRefGoogle Scholar
  5. 5.
    Brandes AA, Franceschi E, Tosoni A, et al. (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26: 2192–2197PubMedCrossRefGoogle Scholar
  6. 6.
    Brandsma D, Stalpers L, Taal W, et al. (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9: 453–461PubMedCrossRefGoogle Scholar
  7. 7.
    Brem H, Piantadosi S, Burger PC, et al. (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345: 1008–1012PubMedCrossRefGoogle Scholar
  8. 8.
    Chinot OL, Barrie M, Frauger E, et al. (2004) Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in elderly populations. Cancer 100: 2208–2214PubMedCrossRefGoogle Scholar
  9. 9.
    Chinot OL, Barrie M, Fuentes S, et al. (2007) Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25: 1470–1475PubMedCrossRefGoogle Scholar
  10. 10.
    Drappatz J, Schiff D, Kesari S, et al. (2007) Medical management of brain tumor patients. Neurol Clin 25: 1035–1071, ixPubMedCrossRefGoogle Scholar
  11. 11.
    Ducray F, Honnorat J (2007) What type of adjuvant chemotherapy should be proposed for the initial treatment of glioblastoma? Presse Med 36: 1249–1254PubMedCrossRefGoogle Scholar
  12. 12.
    Furnari FB, Fenton T, Bachoo RM, et al. (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21: 2683–2710PubMedCrossRefGoogle Scholar
  13. 13.
    Glantz MJ, Cole BF, Forsyth PA, et al. (2000) Practice parameter: anticonvulsivant prophylaxis in patients with newly diagnosed brain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 54: 1886–1893PubMedGoogle Scholar
  14. 14.
    Gorlia T, van den Bent MJ, Hegi ME, et al. (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 9: 29–38PubMedCrossRefGoogle Scholar
  15. 15.
    Hegi ME, Diserens AC, Gorlia T, et al. (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352: 997–1003PubMedCrossRefGoogle Scholar
  16. 16.
    Hegi ME, Liu L, Herman JG, et al. (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26: 4189–4199PubMedCrossRefGoogle Scholar
  17. 17.
    Jain RK, di Tomaso E, Duda DG, et al. (2007) Angiogenesis in brain tumors. Nat Rev Neurosci 8: 610–622PubMedCrossRefGoogle Scholar
  18. 18.
    Keime-Guibert F, Chinot O, Taillandier L, et al. (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356: 1527–1535PubMedCrossRefGoogle Scholar
  19. 19.
    Lee JC, Vivanco I, Beroukhim R, et al. (2006) Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med 3: e485PubMedCrossRefGoogle Scholar
  20. 20.
    Liu G, Yuan X, Zeng Z, et al. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5: 67PubMedCrossRefGoogle Scholar
  21. 21.
    Louis DN, Ohgaki H, Wiestler OD, et al. (2007) The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol 114: 97–109PubMedCrossRefGoogle Scholar
  22. 22.
    Marie Y, Carpentier AF, Omuro AM, et al. (2005) EGFR tyrosine-kinase domain mutations in human gliomas. Neurology 64: 1444–1445PubMedGoogle Scholar
  23. 23.
    Mirimanoff RO, Gorlia T, Mason W, et al. (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 24: 2563–2569PubMedCrossRefGoogle Scholar
  24. 24.
    Murat A, Migliavacca E, Gorlia T, et al. (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26: 3015–3024PubMedCrossRefGoogle Scholar
  25. 25.
    Parsons DW, Jones S, Zhang X, et al. (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807–1812PubMedCrossRefGoogle Scholar
  26. 26.
    Piccirillo SG, Reynolds BA, Zanetti N, et al. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumor-initiating cells. Nature 444: 761–765PubMedCrossRefGoogle Scholar
  27. 27.
    Roa W, Brasher PM, Bauman G, et al. (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22: 1583–1588PubMedCrossRefGoogle Scholar
  28. 28.
    Singh SK, Clarke ID, Hide T, et al. (2004) Cancer stem cells in nervous system tumors. Oncogene 23: 7267–7273PubMedCrossRefGoogle Scholar
  29. 29.
    Stommel JM, Kimmelman AC, Ying H, et al. (2007) Coactivation of receptor tyrosinekinases affects the response of tumor cells to targeted therapies. Science 318: 287–290PubMedCrossRefGoogle Scholar
  30. 30.
    Stupp R, Mason WP, van den Bent MJ, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987–996PubMedCrossRefGoogle Scholar
  31. 31.
    Taillibert S, Laigle-Donadey F, Sanson M (2004) Palliative care in patients with primary brain tumors. Curr Opin Oncol 16: 587–592PubMedCrossRefGoogle Scholar
  32. 32.
    The Cancer Genome Atlas Network Project (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061–1068CrossRefGoogle Scholar
  33. 33.
    Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25: 4722–4729PubMedCrossRefGoogle Scholar
  34. 34.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359: 492–507PubMedCrossRefGoogle Scholar
  35. 35.
    Westphal M, Hilt DC, Bortey E, et al. (2003) A phase III trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel® wafers) in patients with primary malignant glioma. Neuro Oncol 5: 79–88PubMedCrossRefGoogle Scholar
  36. 36.
    Wong ET, Hess KR, Gleason MJ, et al. (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17: 2572–2578PubMedGoogle Scholar
  37. 37.
    www.cbtrus.org Central Brain Tumor Registry of the United States

Copyright information

© Springer Verlag France 2009

Authors and Affiliations

  1. 1.Service de neuro-oncologie, groupe hospitalier Est, Inserm U842université Claude-Bernard-Lyon-ILyonFrance
  2. 2.Unitéde neuro-oncologie, Inserm URM 912, CHU de La Timoneuniversité de la MéditerranéeMarseilleFrance

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