Abstract Diffuse midline glioma (DMG) accounts for 10% of pediatric cancers of the central nervous system. Despite extensive research and clinical trials, there is still no effective treatment for children diagnosed with DMG. The prognosis remains poor with a median survival time of 9–12 months. Single-agent therapies have largely failed, and surgical resection is not feasible due to the invasive nature of tumors and their sensitive brain location. The current standard of care for DMGs involves radiotherapy (RT) followed by enrollment in clinical trials. Recently, two mitochondria-targeting drugs, ONC201 and ONC206, have advanced to Phase 3 and Phase 1 clinical trials, respectively, under the Pacific Pediatric Neuro-Oncology Consortium (PNOC). While these drugs demonstrate robust anti-tumor activity in preclinical models and initial clinical responses, resistance and relapse remain common challenges. Similarly, RT significantly delays DMG progression but offers only transient effects. Resistance mechanisms are frequently encoded in the genome; however, adaptive or non-genetic resistance mechanisms, often mediated by protein phosphorylation cascades, also enable cancer cell survival. Despite their clinical relevance, identifying hyperactive kinases and their associated signaling pathways in cancer cells or tumors remains a technical hurdle. To address this, our laboratory has developed an innovative phospho-reactome mapping system. Using this advanced platform, we profiled 40 samples (cell extracts + xenografted tumors) and identified specific phospho-catalytic circuits that allow DMG cells to overcome the effects of RT or ONC201/206 treatment. Notably, we discovered a shared set of hyperactive kinases in treated cells and tumors, including MET, AURK, NME, AKT, CAMK2, JNK and ROCK. Many of these kinases are known to drive pro-survival signaling networks and represent clinically actionable vulnerabilities. Importantly, our synergy studies ( 400 assays) reveal that targeting these kinases induces synthetic lethality when combined with RT or ONC201/206 treatment in cell culture models. We are translating these findings into in vivo studies using patient-representative mouse models to evaluate the therapeutic efficacy of these combination strategies.
Coppé et al. (Fri,) studied this question.
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