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Medulloblastoma: Therapy and biologic considerations

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Abstract

Tremendous strides have been made in both the treatment and the biologic understanding of medulloblastoma. Present optimal treatment can cure most medulloblastoma patients. A substantial minority of patients, however, will have recurrent or progressive disease. Recent studies have demonstrated that the success of treatment is not simply a matter of chance, but rather can be predicted based on specific biologic markers. These markers predict outcome independent of clinical staging and make clear that medulloblastomas are a biologically diverse group of tumors with variable clinical behavior. Molecular biologic investigation, including replication of tumorigenesis in transgenic mice, has further elucidated the complex biology of medulloblastoma. Current standard and investigational treatments, however, do not yet make use of biologic markers that predict risk of recurrence. Practical limitations have slowed the pace at which treatment paradigms can be revised to incorporate biologic insights. Mouse medulloblastoma models may provide an important bridge between biologic investigation and the development of new therapeutic approaches.

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References and Recommended Reading

  1. Rood BR, Macdonald TJ, Packer RJ: Current treatment of medulloblastoma: recent advances and future challenges. Semin Oncol 2004, 31:666–675. A comprehensive introductory review of the diagnosis, treatment, and biologic investigation of medulloblastoma.

    Article  PubMed  Google Scholar 

  2. Chatty EM, Earle KM: Medulloblastoma. A report of 201 cases with emphasis on the relationship of histologic variants to survival. Cancer 1971, 28:977–983.

    Article  PubMed  CAS  Google Scholar 

  3. Evans AE, Jenkin RD, Sposto R, et al.: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 1990, 72:572–582.

    PubMed  CAS  Google Scholar 

  4. Tait DM, Thornton-Jones H, Bloom HJ, et al.: Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer. 1990, 26:464–469.

    PubMed  CAS  Google Scholar 

  5. Jakacki RI: Treatment strategies for high-risk medulloblastoma and supratentorial primitive neuroectodermal tumors. Review of the literature. J Neurosurg. 2005, 102(Suppl 1):44–52.

    PubMed  Google Scholar 

  6. Wolden SL, Dunkel IJ, Souweidane MM, et al.: Patterns of failure using a conformal radiation therapy tumor bed boost for medulloblastoma. J Clin Oncol 2003, 21:3079–3083.

    Article  PubMed  Google Scholar 

  7. Douglas JG, Barker JL, Ellenbogen RG, et al.: Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure. Int J Radiat Oncol Biol Phys 2004, 58:1161–1164.

    PubMed  Google Scholar 

  8. Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol 1999, 17:2127–2136.

    PubMed  CAS  Google Scholar 

  9. Gardner SL: Application of stem cell transplant for brain tumors. Pediatr Transplant 2004, 8(Suppl 5):28–32.

    Article  PubMed  Google Scholar 

  10. Chan AW, Tarbell NJ, Black PM, et al.: Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery 2000, 47:623–631.

    Article  PubMed  CAS  Google Scholar 

  11. Kunschner LJ, Kuttesch J, Hess K, et al.: Survival and recurrence factors in adult medulloblastoma: the M.D. Anderson Cancer Center experience from 1978 to 1998. Neurooncology 2001, 3:167–173.

    CAS  Google Scholar 

  12. Tabori U, Sung L, Hukin J, et al.: Canadian Pediatric Brain Tumor Consortium. Medulloblastoma in the second decade of life: a specific group with respect to toxicity and management: a Canadian Pediatric Brain Tumor Consortium Study. Cancer 2005, 103:1874–1880.

    Article  PubMed  Google Scholar 

  13. Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 2001, 19:3470–3476.

    PubMed  CAS  Google Scholar 

  14. Mulhern RK, Kepner JL, Thomas PR, et al.: Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin Oncol 1998, 16:1723–1728.

    PubMed  CAS  Google Scholar 

  15. Hart MN, Earle KM: Primitive neuroectodermal tumors of the brain in children. Cancer 1973, 32:890–897.

    Article  PubMed  CAS  Google Scholar 

  16. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 1983, 42:1–15.

    PubMed  CAS  Google Scholar 

  17. Rorke LB: Experimental production of primitive neuroectodermal tumors and its relevance to human neuro-oncology. Am J Pathol 1994, 144:444–448.

    PubMed  CAS  Google Scholar 

  18. Broniscer A, Nicolaides TP, Dunkel IJ, et al.: High-dose chemotherapy with autologous stem-cell rescue in the treatment of patients with recurrent non-cerebellar primitive neuroectodermal tumors. Pediatr Blood Cancer. 2004, 42:261–267.

    Article  PubMed  Google Scholar 

  19. Reddy AT, Janss AJ, Phillips PC, et al.: Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 2000, 88:2189–2193.

    Article  PubMed  CAS  Google Scholar 

  20. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002, 415:436–442. This investigation used comprehensive gene expression studies to establish biologic differences between PNETs in different regions of the central nervous system. Biologic features predicting clinical outcome in retrospective series were also determined.

    Article  PubMed  CAS  Google Scholar 

  21. Russo C, Pellarin M, Tingby O, et al.: Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 1999, 86:331–339.

    Article  PubMed  CAS  Google Scholar 

  22. Rutkowski S, Bode U, Deinlein F, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005, 352:978–986. In this study, infants were treated with multimodal chemotherapy in an attempt to spare them exposure to radiation therapy. The studied regimen was remarkably more effective than previous treatments in allowing infants to avoid radiation therapy. The study population was exceptional for its high proportion of patients with desmoplastic tumor, and infants in this subgroup fared far better than those with classic histology.

    Article  PubMed  CAS  Google Scholar 

  23. Giordana MT, D’Agostino C, Pollo B, et al.: Anaplasia is rare and does not influence prognosis in adult medulloblastoma. J Neuropathol Exp Neurol 2005, 64:869–874.

    Article  PubMed  Google Scholar 

  24. Eberhart CG, Kepner JL, Goldthwaite PT, et al.: Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 2002, 94:552–560. This study correlates degree of anaplasia with clinical outcome, demonstrating intrinsic heterogeneity within the diagnosis of medulloblastoma.

    Article  PubMed  Google Scholar 

  25. Lamont JM, McManamy CS, Pearson AD, et al.: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 2004, 10:5482–5493. These investigators determined prognostically relevant subgroups using FISH and histopatholgy.

    Article  PubMed  CAS  Google Scholar 

  26. Gajjar A, Hernan R, Kocak M, et al.: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 2004, 22:984–993. The authors propose a stratification scheme based on ERBB2 expression meausred by Western blot combined with clinical staging. They demonstrate both the feasibility of Western blot analysis of brain tumor samples, and the existence of biologic diversity.

    Article  PubMed  CAS  Google Scholar 

  27. Ray A, Ho M, Ma J, et al.: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 2004, 10:7613–7620. This study documents multiple biologic markers of clinical prognosis, supporting the view of medulloblastoma as a heterogeneous, potentially predictable clinical and biologic entity.

    Article  PubMed  CAS  Google Scholar 

  28. Pan E, Pellarin M, Holmes E, et al.: Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 2005, 11:4733–4740. In this retrospective study, the presence of isochromosome 17q marked a group of high-risk patients with no long-term survivors, again demonstrating the predictive value of biologic criteria.

    Article  PubMed  CAS  Google Scholar 

  29. Rorke LB, Trojanowski JQ, Lee VM, et al.: Primitive neuroectodermal tumors of the central nervous system. Brain Pathol 1997, 7:765–784.

    PubMed  CAS  Google Scholar 

  30. Katsetos CD, Del Valle L, Legido A, et al.: On the neuronal/ neuroblastic nature of medulloblastomas: a tribute to Pio del Rio Hortega and Moises Polak. Acta Neuropathol (Berlin) 2003, 1:1–13.

    Google Scholar 

  31. Kho AT, Zhao Q, Cai Z, et al.: Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers. Genes Dev 2004, 18:629–640.

    Article  PubMed  CAS  Google Scholar 

  32. Fogarty MP, Kessler JD, Wechsler-Reya RJ: Morphing into cancer: the role of developmental signaling pathways in brain tumor formation. J Neurobiol 2005, 64:458–475.

    Article  PubMed  CAS  Google Scholar 

  33. Pietsch T, Taylor MD, Rutka JT: Molecular pathogenesis of childhood brain tumors. J Neurooncol 2004, 70:203–215.

    Article  PubMed  Google Scholar 

  34. Buhren J, Christoph AH, Buslei R, et al.: Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features: evidence for a medulloblastoma subtype derived from the external granule cell layer. J Neuropathol Exp Neurol 2000, 59:229–240.

    PubMed  CAS  Google Scholar 

  35. Salsano E, Pollo B, Eoli M, et al.: Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma sub-types. Neurosci Lett 2004, 370(2–3):180–185. The authors relate desmoplastic medulloblastoma to specific cells of the developing cerebellum, placing the heterogeneity of medulloblastoma in a developmental perspective.

    Article  PubMed  CAS  Google Scholar 

  36. Gershon TR, Oppenheimer O, Chin SS, et al.: Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia 2005, 7:575–584. The investigators also relate histololgic subtype to development, documenting expression of the dorsal neuroectodermal transcription factor, PAX3, in the classic but not desmoplastic medulloblastoma.

    Article  PubMed  CAS  Google Scholar 

  37. Katsetos CD, Herman MM, Krishna L, et al.: Calbindin-D28k in subsets of medulloblastomas and in the human medulloblastoma cell line D283 Med. Arch Pathol Lab Med 2002, 119:734–743. In this publication, cells of classic medulloblastomas express a marker specific to cells of the developing cerebellum, again demonstrating developmental correlation with medulloblastoma subtype.

    Google Scholar 

  38. Katsetos CD, Frankfurter A, Christakos S, et al.: Differential localization of class III, beta-tubulin isotype and calbindin-D28k defines distinct neuronal types in the developing human cerebellar cortex. J Neuropathol Exp Neurol 1993, 52:655–666.

    PubMed  CAS  Google Scholar 

  39. Stoykova A, Gruss P: Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci 1994, 14(3 Pt 2):1395–1412.

    PubMed  CAS  Google Scholar 

  40. Lum L, Beachy PA: The Hedgehog response network: sensors, switches, and routers. Science 2004, 304:1755–1759.

    Article  PubMed  CAS  Google Scholar 

  41. Goodrich LV, Milenkovic L, Higgins KM, et al.: Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277:1109–1113.

    Article  PubMed  CAS  Google Scholar 

  42. Weiner HL, Bakst R, Hurlbert MS, et al.: Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1. Cancer Res 2002, 62:6385–6389.

    PubMed  CAS  Google Scholar 

  43. Rao G, Pedone CA, Valle LD, et al.: Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene 2004, 23:6156–6162.

    Article  PubMed  CAS  Google Scholar 

  44. Rao G, Pedone CA, Coffin CM, et al.: c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice. Neoplasia 2003, 5:198–204.

    PubMed  CAS  Google Scholar 

  45. Hallahan AR, Pritchard JI, Hansen S, et al.: The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 2004, 64:7794–7800. This work represents a novel application of mouse model medulloblastomas. The investigators analyzed gene expression in tumors induced through Shh pathway activity, looking for recruitment of additional pathways. They found that genes of the Notch pathway were upregulated, then documented the involvement of this signaling pathway in human medulloblastoma. Insight into the human tumor was thus developed by analyzing the biology of the mouse model.

    Article  PubMed  CAS  Google Scholar 

  46. Romer JT, Kimura H, Magdaleno S, et al.: Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 2004, 6:229–240. This work represents the first published use of mouse medulloblastoma as a preclinical model for testing a novel therapy.

    Article  PubMed  CAS  Google Scholar 

  47. Lin W, Kemper A, McCarthy KD, et al.: Interferon-gamma induced medulloblastoma in the developing cerebellum. J Neurosci 2004, 24:10074–10083. This article describes mouse medulloblastomas induced by ectopic expression of genes outside of the Shh pathway. This model proceeds through Shh activation.

    Article  PubMed  CAS  Google Scholar 

  48. Marino S, Vooijs M, van Der Gulden H, et al.: Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev 2000, 14:994–1004.

    PubMed  CAS  Google Scholar 

  49. Gan DD, Reiss K, Carrill T, et al.: Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus. Oncogene 2001, 20:4864–4870. This article describes mouse medulloblastomas induced by ectopic expression of genes outside of the Shh pathway.

    Article  PubMed  CAS  Google Scholar 

  50. Gilbertson RJ, Gajjar A: Molecular biology of medulloblastoma: will it ever make a difference to clinical management? J Neurooncol 2005, 75:273–278.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, 10021, New York, NY, USA

    Timothy R. Gershon MD, PhD

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  1. Timothy R. Gershon MD, PhD
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  2. Orren J. Becher MD
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Correspondence to Timothy R. Gershon MD, PhD.

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Gershon, T.R., Becher, O.J. Medulloblastoma: Therapy and biologic considerations. Curr Neurol Neurosci Rep 6, 200–206 (2006). https://doi.org/10.1007/s11910-006-0006-y

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