Medulloblastoma: From Molecular Pathology to Therapy

Abstract

Medulloblastoma is the most common malignant tumor of central nervous system in children.Patients affected by medulloblastoma may be categorized as high-risk and standard-risk patients, based on the clinical criteria and histologic features of the disease. Currently, multimodality treatment, including surgery, radiotherapy, and chemotherapy is considered as the most effective strategy against these malignant cerebellar tumors of the childhood. Despite the potential poor outcomes of these lesions, the 5-year survival stands, at present, at 70% to 80% for standard-risk patients, whereas high-risk patients have a 5-year survival of 55% to 76%. Attempts to further reduce the morbidity and mortality associated with medulloblastoma have been restricted by the toxicity of conventional treatments and the infiltrative nature of the disease. Over the past decade, new discoveries in molecular biology have revealed new insights in signaling pathways regulating medulloblastoma tumor formation. Recent advances in the molecular biology of medulloblastoma indicate that the classification of these embryonal tumors, solely based on histology and clinical criteria, may not be adequate enough. Better understanding of the growth control mechanisms involved in the development and progression of medulloblastoma will allow a better classification, leading to the improvement of the existing therapies, as well as to the development of new therapeutic approaches.

Bone morphogenetic protein-7 is a MYC target with prosurvival functions in childhood medulloblastoma

“…A therapeutic approach interfering with activation of the BMP pathway was investigated here, for the first time, in MB cells and would represent one attractive strategy, to be considered in combination with targeting of sonic hedgehog and Wnt pathways (Chen et al, 2002;Romer and Curran, 2005;Luo et al, 2007;Rossi et al, 2008). Additional investigations on the role of other BMP family members will emphasize the relevance of the whole pathway in the development of MB.…”

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

“…Medulloblastoma, an embryonic tumor of the cerebellum, constitutes the most frequent malignant brain tumor of childhood (Kleihues et al, 2002;Rossi et al, 2008). As conventional therapies and risk stratification have already been optimized in recent years (Rutkowski et al, 2007), experimental therapeutics are likely critical to improve the still poor prognosis of children with high-risk medulloblastoma.…”

Medulloblastoma – Genetic Alterations

“…Other molecular markers beside the above three identified groups is the amplification of MYC family (MYC and MYCN proto-oncogenes), that account for 4-15% of MBs (Rossi et al 2008;McCabe et al 2006). MYCN is an early transcriptional target of the SHH pathway and activation by SHH promotes the expression of the cell cycle proteins cyclinD1 and CyclinD2 leading to GCP proliferation (Behesti amd Marino 2009).…”

“…It is the most common malignant brain tumor in children it represents 15-30% of all pediatric brain tumors, with 85% of MBs being diagnosed in patients younger then 18 years of age. The peak incidence occurs between the ages 3-9 years, with about 35% metastasis disease (Crawford et al, 2007;Polkinghorn and Tarbell 2007;Rossi et al, 2008). In contrast, medulloblastoma is rare in adults and accounts for less than1% of primary intracranial malignancies in this age group (Brandes et al 2009;Louis 2007;Padovani et al 2007).…”