Molecular-Targeted Therapies for Childhood Medulloblastoma

Current risk stratification of standard medulloblastoma patients is based on clinical risk factors (age between 3 and 22 years, absence of metastasis and gross total or near gross total surgical excision). In the prospective randomised HIT-SIOP PNET4 trial, two risk groups were identified according to the presence or absence of β-catenin accumulation, significant postoperative residual tumor, anaplastic/large cell histology, and c-MYC or N-MYC DNA amplification, respectively. The next European standard risk medulloblastoma trial, using biological and clinical factors for treatment stratification, is under preparation.

The use of drugs that target cell-signalling pathways – implicated in the medulloblastoma formation – may further improve survival. In different phase I/II trials, drugs with anti-angiogenetic activity (cediranib maleate – AZD2171, bevacizumab, enzastaurin – LY317615, and semoxind – SU5416), a small molecule that inhibits the NOTCH pathway – MK0752, an inhibitor of ERBB receptor signalling lapatinib – GW572016, and a promising antagonist of the Hedgehog signalling pathway – GDC-0449, are investigated.

In order to improve survival and decrease long-term side effects in childhood medulloblastoma, molecular biology may contribute to therapeutic strategies in future by improving risk group definition and allowing escalation or intensification of treatment, and by identifying new targets for novel therapeutic agents, providing alternatives to conventional radiochemotherapeutical approaches.