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Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from
Sabine Mueller1, Cassie Kline2, Andrea Franson3
1Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, California, USA.
Abstract:
Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.
Insights
ONC201 and paxalisib combination therapy shows promise for pediatric diffuse midline glioma (DMG). This approach targets tumor cell metabolism, paving the way for the PNOC022 clinical trial and future DMG research.
Area of Science:
- Oncology
- Pediatric Neuro-oncology
- Molecular Biology
Background:
- Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor with limited treatment options.
- H3K27M oncohistones, present in ~80% of DMGs, alter tumor cell epigenetics and metabolism.
- Previous research demonstrated preclinical efficacy of targeting tumor cell metabolism.
Purpose of the Study:
- To present the rationale for the first diffuse midline glioma-specific platform trial, PNOC022.
- To outline a combination therapy strategy targeting key metabolic pathways in DMG.
- To discuss future directions for clinical trials in DMG.
Main Methods:
- Preclinical studies showed efficacy of targeting oxidative phosphorylation with ONC201 (ClpP activator) and glycolysis with paxalisib (PI3K/mTOR inhibitor).
- Combination therapy aims to induce metabolic distress in DMG cells.
- Design of the PNOC022 (NCT05009992) platform trial based on these findings.
Main Results:
- The combination of ONC201 and paxalisib demonstrated preclinical efficacy in targeting DMG metabolism.
- This preclinical success informed the design of the PNOC022 trial.
Conclusions:
- The PNOC022 trial represents a novel, DMG-specific platform for evaluating targeted therapies.
- Future DMG clinical trials should consider biomarkers (liquid, microbiome, genomic), quality-of-life endpoints, and advanced imaging.
- This work provides a framework for advancing therapeutic strategies against pediatric diffuse midline glioma.
