Oncologie

, Volume 11, Issue 2, pp 72–77

Nouvelles thérapeutiques ciblées dans les glioblastomes

Synthèse / Review Article

Résumé

Le traitement standard actuel des glioblastomes associe exérèse chirurgicale, radiothérapie et chimiothérapie. Son efficacité reste limitée, avec une médiane de survie de 15 mois environ. Depuis quelques années, de nouveaux traitements dits « ciblés » sont venus renforcer l’arsenal thérapeutique déjà existant. Le développement de ces nouvelles molécules s’appuie sur la connaissance des caractéristiques biologiques et moléculaires des cellules cancéreuses, comme la surexpression du récepteur à l’EGF, la sécrétion de PDGF, l’activation des voies de transduction PI3K/Akt, mTOR et Ras/Raf ou la sécrétion de protéases qui dégradent la matrice extracellulaire. Les essais cliniques de ces molécules dans les glioblastomes restent pour le moment décevants. En revanche, les premiers résultats cliniques avec les agents anti-angiogéniques sont plutôt positifs, laissant espérer une amélioration du pronostic des tumeurs cérébrales dans les années qui viennent.

Mots clés

Glioblastomes Essais cliniques Nouvelles approches thérapeutiques 

New-targeted therapies for glioblastoma treatment

Abstract

The efficacy of the standard treatment for glioblastomas (surgical resection combined with radiotherapy and chemotherapy) is so far somewhat limited with a median survival rate of about 15 months. The development of new therapeutic approaches is therefore needed. In recent years, new-targeted drugs have been developed to strengthen the therapeutic arsenal in cancer treatment. Molecular targets are based on the biological and molecular characteristics of the cancer cell, such as hyperexpression of the EGF receptor, activation of the PI3K/Akt and Ras/Raf pathways. Unfortunately, results from glioblastoma trials have been disappointing so far. On the other hand, early clinical results using antiangiogenic agents appear very promising. It can be hoped that in the next few years these agents might transform the dismal prognosis of glioblastomas.

Keywords

Glioblastoma Clinical trial New therapeutic approaches Targeted therapies 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Références

  1. 1.
    Bachelor TT, Sorensen AG, Di Tomaso E, et al. (2007) AZD2171, a pan-VEGF receptor tyrosine-kinase inhibitor, normalizes tumor vasculature and alleviates oedema in glioblastoma patients. Cancer Cell 11: 83–95CrossRefGoogle Scholar
  2. 2.
    Behin A, Hoang-Xuan K, Carpentier AF, et al. (2003) Primary brain tumors in adults. Lancet 361: 323–31PubMedCrossRefGoogle Scholar
  3. 3.
    Bogdahn U, Oliushine VE, Parfenov VE, et al. (2006) Results of G004, a phase IIb study in recurrent glioblastoma patients with the TGF-beta-2 targeted compound AP. ASCO Annual Meeting Proceedings Part I 24(18S): 1553Google Scholar
  4. 4.
    Brown PD, Krishnan S, Sarkaria J, et al. (2008) A phase II trial (no 177) of erlotinib and temozolomide (TMZ) combined with radiation therapy (RT) in glioblastoma multiform (GBM). ASCO Annual Meeting Proceedings: abstract no 2016Google Scholar
  5. 5.
    Butowski N, Lamborn K, Chang S, et al. (2008) Phase I/II study of enzastaurin (ENZ) plus temozolomide (TMZ) and radiation therapy (XRT) in patients (PTS) with glioblastoma multiform (GBM) or gliosarcoma (GS). EANO: abstract no 41Google Scholar
  6. 6.
    Carpentier A, Laigle-Donadey F, Zohar S, et al. (2006) Phase I trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 8: 60–66PubMedCrossRefGoogle Scholar
  7. 7.
    Chang SM, Wen P, Cloughesy TF, et al. (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiform (GBM). Invest New Drugs 23: 357–361PubMedCrossRefGoogle Scholar
  8. 8.
    Chen W, Delaloye S, Silverman DHS, et al. (2007) Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F]fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 25: 4714–4721PubMedCrossRefGoogle Scholar
  9. 9.
    Cloughesy TF, Wen PY, Robins HI, et al. (2006) Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing anti-epileptic drugs: a North American Brain Consortium Study. J Clin Oncol 24: 3651–3656PubMedCrossRefGoogle Scholar
  10. 10.
    Cloughesy T, Prados M, Wen P, et al. (2008) A phase II, randomized, noncomparative clinical trial of bevacizumab alone or in combination with CPT-11 prolongs 6-month progression-free survival in recurrent, treatment-refractory glioblastoma. ASCO Annual Meeting Proceedings: abstract no 2010bGoogle Scholar
  11. 11.
    Combs SE, Schulz-Ertner D, Hartmann C, et al. (2008) Phase I/II study of cetuximab plus temozolomide as radiochemotherapy for primary glioblastoma. (GERT) ASCO Annual Meeting Proceedings: abstract no 2077Google Scholar
  12. 12.
    Das CM, Aguilera D, Vasquez H, et al. (2007) Valproic acid induces p21 and topoisomerase II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol 85: 159–170PubMedCrossRefGoogle Scholar
  13. 13.
    Franceschi E, Cavallo G, Lonardi S, 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: 1047–1051PubMedCrossRefGoogle Scholar
  14. 14.
    Friedman HS, Desjardins A, Vredenburgh JJ, et al. (2008) Phase II trial of erlotinib plus sirolimus for recurrent glioblastoma multiform (GBM). ASCO Annual Meeting: abstract no 2062Google Scholar
  15. 15.
    Furnari FB, Fenton T, Bachoo RM, et al. (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21: 2683–2710PubMedCrossRefGoogle Scholar
  16. 16.
    Galanis E, Buckner JC, Maurer MJ. (2005) Phase II trail of temsirolimus (CCI-779) in recurrent glioblastoma multiform: a North Central Cancer Treatment Group Study. J Clin Oncol 23: 5294–5304PubMedCrossRefGoogle Scholar
  17. 17.
    Goudar RK, Shi Q, Hjelmeland MD, et al. (2005) Combination therapy of inhibitors of epidermal growth factor receptorvascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4: 101–112PubMedGoogle Scholar
  18. 18.
    Guiu S, Taillibert O, Chinot O, et al. (2008) Bévacizumab-irinotécan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d’une étude multicentrique de l’Anocef. Rev Neurol 164: 588–594PubMedCrossRefGoogle Scholar
  19. 19.
    Kil KE, Ding YS, Lin KS, et al. (2007) Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec). Nucl Med Biol 34: 153–163PubMedCrossRefGoogle Scholar
  20. 20.
    Kim MS, Blake M, Baek JH, et al. (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63: 7291–300PubMedGoogle Scholar
  21. 21.
    Kirkpatrick JP, Rich JN, Vredenburg JJ, et al. (2008) Final report: phase I trial of imatinib mesylate, hydroxyurea, and vatalanib for patients with recurrent malignant gliomas (GM). ASCO Annual Meeting Proceedings. Abstract no 2057Google Scholar
  22. 22.
    Lai A, Filka E, McGibbon B, et al. (2008). Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiform: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys (in press)Google Scholar
  23. 23.
    Levin VA, Phuphanich S, Glantz ML, et al. (2002) Randomized phase II study of temozolomide with and without the metalloprotease inhibitor prinomastat in patients with glioblastoma multiform following best surgery and radiation therapy. Am Soc Clin Oncol, Annual Meeting: abstract no 21Google Scholar
  24. 24.
    Maron R, Vredenburgh JJ, Desjardins A, et al. (2008) Bevacizumab and daily temozolomide for recurrent glioblastoma multiform (GBM). ASCO Annual Meeting: abstract no 2074Google Scholar
  25. 25.
    Melinghoff IK, Wang MY, Vivanco I, et al. (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353: 2012–2024CrossRefGoogle Scholar
  26. 26.
    Muggeri AD, Diez BD (2008) Nimotuzumab with chemotherapy in recurrent malignant glioma: analysis of a case series. EANO: abstract no 59Google Scholar
  27. 27.
    Nabors LB, Mikkelsen T, Rosenfeld SS, et al. (2007) Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. J Clin Oncol 25: 1651–1657PubMedCrossRefGoogle Scholar
  28. 28.
    Neyns B, Sadones J, Joosens E, et al. (2008) A multicenter stratified phase II study of cetuximab for the treatment of patients with recurrent high-grade glioma. EANO: abstract no 19Google Scholar
  29. 29.
    Norden AD, Young GS, Setayesh K, et al. (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70: 779–787PubMedCrossRefGoogle Scholar
  30. 30.
    Pedeboscq S, L’Azou B, Passagne I, et al. (2008) Cytotoxic and apoptotic effects of bortezomib and gefitinib compared to alkylating agents on human glioblastoma cells. J Exp Ther Oncol 7: 99–111PubMedGoogle Scholar
  31. 31.
    Phuphanich S, Levin VA, Yung WK, et al. (2001) A multicenter, randomized, doubleblind, placebo (PB) controlled trial of marimastat (MT) in patients with glioblastoma multiform (GBM) or gliosarcoma (GS) following completion of conventional, firstline treatment. ASCO Annual Meeting Proceedings: abstract no 205Google Scholar
  32. 32.
    Phuphanich S, Rudnick J, Chu R, et al. (2008) A phase I trial of gefitinib and sirolimus in adults with recurrent glioblastoma multiform (GBM). ASCO Annual Meeting: abstract no 2088Google Scholar
  33. 33.
    Prados MD, Lamborn K, Yung WK, et al. (2006) A phase II trial of irinotecan (CPT-11) in patients with recurrent malignant gliomas: a North American Brain Tumor Consortium Study. Neuro Oncol 8: 189–193PubMedCrossRefGoogle Scholar
  34. 34.
    Quant E, Norden AD, Drappatz J, et al. (2008) Role of a second chemotherapy in recurrent malignant gliomas patients who progress on bevacizumab-containing regimen. ASCO Annual Meeting: abstract no 2008Google Scholar
  35. 35.
    Raymond E, Brandes A, Van Oosterom A, et al. (2004) Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: an EORTC NDDG/BTG Intergroup Study. ASCO Annual Meeting: abstract no 1501Google Scholar
  36. 36.
    Reardon DA, Egorin MJ, Quinn JA, et al. (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiform. J Clin Oncol 23: 9359–9368PubMedCrossRefGoogle Scholar
  37. 37.
    Rich JN, Reardon DA, Peery T, et al. (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22: 133–142PubMedCrossRefGoogle Scholar
  38. 38.
    Rich JN, Desjardins A, Sathornsumetee S, et al. (2008) Phase II study of bevacizumab and etoposide in patients with recurrent malignant gliomas. ASCO Annual Meeting: abstract no 2022Google Scholar
  39. 39.
    Stark-Vance V (2005) Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. World Federation of Neuro-oncology MeetingGoogle Scholar
  40. 40.
    Stupp R, Mason WP, Van Den Bent J, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987–996PubMedCrossRefGoogle Scholar
  41. 41.
    Van Den Bent MJ, Brandes AA, Rampling R, et al. (2007) Randomized phase II trial of erlotinib versus temozolomide or BCNU in recurrent glioblastoma multiform (GBM): EORTC 26034. ASCO Annual Meeting Proceedings: abstract 2005Google Scholar
  42. 42.
    Vredenburgh JJ, Desjardins A, Hemdon JE 2nd, et al. (2007a) Bevacizumab plus irinotecan in recurrent glioblastoma multiform. J Clin Oncol 25: 4722–4729PubMedCrossRefGoogle Scholar
  43. 43.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, et al. (2007b) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13: 1253–1259PubMedCrossRefGoogle Scholar
  44. 44.
    Wick W, Puduvalli VK, Chamberlain M, et al. (2008) Enzastaurin (ENZ) versus lomustine (CCNU) in the treatment of recurrent, intracranial glioblastoma (GBM): a phase III study. EANO: abstract no 22Google Scholar
  45. 45.
    Wong ET, Hess KR, Gleason MJ, et al. (1999) Outcomes and prognostic factors in recurrent gliomas patients enrolled onto phase II clinical trials. J Clin Oncol 17: 2572–2578PubMedGoogle Scholar
  46. 46.
    Yin D, Ong JM, Hu J, et al. (2007) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of gliomas cells in vitro and in vivo. Clin Cancer Res 13: 1045–52PubMedCrossRefGoogle Scholar
  47. 47.
    Yung WK, Albright RE, Olson TL, et al. (2000) A phase II study of temozolomide versus pracarbazine in patients with glioblastoma multiform at first relapse. Br J Cancer 83: 588–593PubMedCrossRefGoogle Scholar
  48. 48.
    Zuniga RM, Torcuator R, Jain R, et al. (2008) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol (in press)Google Scholar

Copyright information

© Springer Verlag France 2009

Authors and Affiliations

  1. 1.Service de neurologie de l’hôpital AvicenneAssistance publique-Hôpitaux de ParisBobignyFrance
  2. 2.UFR de santé, médecine et biologie humaine de Bobignyuniversité Paris-XIIIBobignyFrance

Personalised recommendations