Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma.

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Targeted Sequencing of Malignant Supratentorial Pediatric Brain Tumors Demonstrates a High Frequency of Clinically Relevant Mutations.

Pediatric brain tumors cause more deaths than any other childhood malignancy, and the identification of potentially actionable genomic alterations in this rare heterogeneous group of tumors may improve treatment and outcome. The genetic landscape of common posterior fossa tumors has been described in the past several years, yet the classification of malignant pediatric supratentorial tumors remains controversial. Next-generation sequencing (NGS) is a promising tool to evaluate multiple genes concurrently. The clinical utility of NGS has not been proven in pediatric brain tumors. We identified patients diagnosed with high-grade supratentorial pediatric brain tumors resected between 2008 and 2012 at our institution. DNA from 12 formalin-fixed paraffin-embedded tumor samples from 9 patients was analyzed, including 3 paired samples from diagnosis and relapse. A panel of 194 cancer-related genes was sequenced using targeted next-generation deep sequencing. Genetic findings were correlated with histology, immunohistochemistry, treatment, and survival. We found one or more pathologic genetic change (mutation, amplification, or deletion) in 8 of 9 (89%) of patients studied. Epidermal Growth Factor Receptor ( EGFR) mutations were found in 3 patients, 2 of which had an exon 20 insertion not previously described in pediatric malignancy. Additional genetic changes were found in EGFR and Platelet-Derived Growth Factor Receptor Alpha ( PDGFRA) at relapse not present in the initial samples. Familial cancer predisposition syndromes were suggested by mutations found in 3 genes in 4 patients, including TP53, MSH2, and CHEK2. Seven of 9 patients in this study died of their disease. In summary, targeted deep sequencing may be used in rare pediatric brain tumors to identify driver mutations for targeted therapy, suggest constitutional and familial testing for cancer predisposition syndromes, and select molecular targets worthy of further study.