Advances in Molecular Targets for the Treatment of Medulloblastomas

Abstract

To present an assortment of molecular targets evident from a variety of signal transduction pathways and downstream effectors, which may have clinical relevance for the treatment of medulloblastomas. Data were archived from MEDLINE, using Boolean-formatted queries on the keywords including: medulloblastoma, pathology, prognosis, classification, tumor regression, inhibition, therapy, clinical trial, therapeutic agent, drug, molecular inhibitor, and signalling pathway. Only the most reputable articles were selected for critical analyses based on the qualitative assessment of the citation index, novelty of the findings and relevance to prospective novel ways of targeted therapies for medulloblastomas. Medulloblastomas are highly aggressive embryonal tumors of the cerebellum, akin to primitive neuroectodermal tumors elsewhere in the brain. Current treatments for medulloblastomas which include a combination of surgery, chemotherapy and radiation, remain challenging especially, for younger patients; however, advances in understanding regulatory pathways in medulloblastomas are crucial to develop more effective therapeutic targets. Evidence showing several molecular and pharmacological targets within key signalling pathways, such as HEDGEHOG, WNT, NOTCH, Receptor Tyrosine Kinase (ERB, IGF-IR, c-MET, PDGF, Estrogen, p75NTR) , their downstream effectors like PI3K/AKT, c-MYC and STAT3, and as well as other targets such as telomerase and cytoskeletal elements, is summarized. All molecular and pharmacological targets have pivotal roles in the pathogenesis of medulloblastomas. Most importantly, these pathways can be effectively pharmacologically targeted to regress the growth of medulloblastomas. Pre-clinical studies were routinely undertaken with a variety of human and murine cell lines and as well as murine models of medulloblastomas. Thus far, two drugs which target the NOTCH and HEDGEHOG signalling have completed Phase I clinical trials, but with evidence of low efficacies; hence, reinforcing the importance of continuing investigations in search of new therapeutic agents and targets. Novel therapies, based on better understanding key biological pathways in medulloblastomas, hold promise for improved treatments in due course among patients with medulloblastomas.