Advances in Molecular Targets for the Treatment of Medulloblastomas

Abstract

Purpose: To present an assortment of molecular targets evident from a variety of signal transduction pathways and downstream e ectors, which may have clinical relevance for the treatment of medulloblastomas.Source: Data were archived from MEDLINE, using Boolean-formatted queries on the keywords including: medulloblastoma, pathology, prognosis, classi cation, 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 ndings and relevance to prospective novel ways of targeted therapies for medulloblastomas.Principal ndings: 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 e ective 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 e ectors 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 e ectively 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. us far, two drugs which target the NOTCH and HEDGEHOG signalling have completed Phase I clinical trials, but with evidence of low e cacies; hence, reinforcing the importance of continuing investigations in search of new therapeutic agents and targets.Conclusion: Novel therapies, based on better understanding key biological pathways in medulloblastomas, hold promise for improved treatments in due course among patients with medulloblastomas.

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

“…In the CNS, STAT3 is a potential target in the prevention and the treatment of medulloblastoma (Ajeawung et al, 2012) and glioblastoma multiforme, the most common and aggressive primary brain tumour (Luwor et al, 2013). STAT3 inhibition also prevents ischaemic brain injury and has a therapeutic potential for ischaemic strokes .…”

Targeting the IGF-Axis in Cultured Pediatric High-Grade Glioma Cells Inhibits Cell Cycle Progression and Survival

“…More recently, Simpson et al showed that IGF-1R targeting increased the radio-sensitivity of pHGG cells, likely through perturbation of the DNA damage response [ 14 ]. Of relevance, IGF-1R was also identified as a therapeutic target in medulloblastoma, a highly aggressive pediatric malignancy of the cerebellum [ 29 , 30 ]. Collectively, the results suggest that IGF-1R targeting may have beneficial therapeutic effects in pediatric brain malignancies, including pHGG.…”

Medulloblastoma development: tumor biology informs treatment decisions

“…Myc inhibition for cancer therapy has been investigated over the years with little success. Nevertheless, agents that target Myc such as S2T1–6OTD, a telomestatin derivative that can bind to the c-Myc promoter, as well as agents that can modulate Myc expression including all- trans -retinoic acid (ATRA), the quassinoid analog NBT-272, the anti-convulsant and HDAC inhibitor-valproic acid (VPA), the polyphenol resveratrol, have shown efficacy in vitro and in mice, and their further investigation in MYC-high MBs may be warranted [76,77]. The availability of three separate Myc-driven mouse models of LCA MB should further aid in such preclinical studies [78–81].…”