Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas

TL;DR

This paper reviews challenges and opportunities in using PI3K/mTOR inhibitors to treat aggressive pediatric brain cancers, focusing on improving treatment strategies.

Contribution

The paper proposes a roadmap for future research on PI3K/mTOR inhibition in pediatric high-grade gliomas, emphasizing combination therapies and patient stratification.

Findings

PI3K/mTOR inhibitors face challenges like poor brain penetration and adaptive resistance.

Combining inhibitors with other therapies requires balancing toxicity and efficacy.

Improved regimen design and patient stratification are critical for better outcomes.

Abstract

Pediatric high-grade glioma (pHGG), including diffuse midline glioma (DMG), are the most aggressive and fatal pediatric cancers. Mutations and amplifications within the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway drive tumor growth, treatment resistance, and poor outcomes. Although PI3K and mTOR have been identified as genetic dependencies in pHGGs, translating this knowledge into effective treatment remains challenging. The blood–brain barrier (BBB) restricts the delivery of most PI3K/mTOR inhibitors and , hence, often show poor CNS penetration. Even when present in the brain, these agents frequently encounter adaptive resistance mechanisms that blunt efficacy. Side effects, including hyperglycemia, rash, and mucositis, further complicate their use and reduce compliance. Encouragingly, novel brain-penetrant PI3K/mTOR inhibitors offer new opportunities for treatment, but combining these agents with other therapies, including chemotherapy, other small molecules, and immunotherapies, requires careful balancing of toxicity and efficacy. Therefore, achieving optimal dosing for each patient remains a significant hurdle. This review examines the promise and pitfalls of targeting the PI3K/mTOR pathway in DMG, including the limitations of available therapies, mechanisms of resistance, and the critical need for improved regimen design. We propose a roadmap to guide future efforts, emphasizing rational combination strategies and better patient stratification to improve survival for children diagnosed with these devastating cancers.

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