An integrated approach to identifying clinically relevant targets in pediatric gliomas.

Abstract

303 ISSN 2045-0907 10.2217/CNS.13.21 © 2013 Future Medicine Ltd CNS Oncol. (2013) 2(4), 303–306 High-grade gliomas (HGGs) are categorized by WHO as grade III–IV glial malignancies and account for roughly 15–20% of all pediatric CNS tumors [1]. For pediatric patients diagnosed with supratentorial HGGs, the 2-year survival rates range from 10 to 30%. The prognosis for patients with diffuse brainstem gliomas is even more dismal, as less than 10% will survive more than 2 years after diagnosis [1]. The current treatment for newly diagnosed pediatric HGGs is safe maximal surgical resection and radiotherapy. The addition of chemotherapy to this regimen is debatable, reflecting the lack of consensus among pediatric neuro-oncologists regarding the optimal protocol/treatment plan for newly diagnosed patients [2]. Despite these efforts, marginal impact has been made on the overall survival rates of these patients. This begs the question: ‘how do we change the way in which we view and treat pediatric HGGs?’ To fully understand the complexities of pediatric HGGs and subsequently identify therapeutic vulnerabilities, we must first understand the full molecular, cellular and physiological context of these malignancies. While it has long been thought that both pediatric and adult gliomas are the same disease affecting different patient populations, recently, multiple groups including the Canadian Paediatric Cancer Genome Consortium and the St Jude Children’s Research Hospital–Washington University in St Louis Pediatric Cancer Genome Project have challenged this notion by revealing striking differences in the mutation spectrum and frequencies between pediatric and adult HGGs [3–11]. The use of high-resolution genomic approaches has uncovered potential therapeutic targets for pediatric gliomas such as PDGFRA, MET and IGF1R (recurrent focal amplification in HGGs and pontine gliomas) [7,10,12], BRAF and CDK2NA (BRAF-V600E mutations with concomitant CDKN2A loss in a subset of malignant astrocytomas) [11] and FGFR1 (intragenic duplications of the tyrosine kinase domain in low-grade gliomas) [3]. Alone, the identification and characterization of the somatic DNA alterations is insufficient. Pediatric HGGs harbor