ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), represent a critical unmet need in pediatric oncology with limited treatment options.
• ONC201, a dual DRD2 antagonist and ClpP agonist, has demonstrated preclinical and early clinical promise in DMG.
• Understanding the molecular mechanisms and genomic influences on ONC201 response is crucial for optimizing treatment strategies.

Purpose of the Study:

• To elucidate the mechanisms by which ONC201 exerts its anti-tumor effects in DIPG.
• To investigate the role of specific genomic alterations (PIK3CA, TP53) in modulating DIPG sensitivity to ONC201.
• To identify potential combination therapies to overcome resistance mechanisms.

Main Methods:

• Systems-biological analysis of ONC201-treated DIPG models.
• Assessment of mitochondrial proteolysis, electron transport chain, and tricarboxylic acid cycle protein levels.
• Genomic profiling to correlate mutations with drug sensitivity.
• Pharmacological inhibition of PI3K/Akt signaling pathway.

Main Results:

• ONC201 induces potent ClpP agonism, leading to proteolysis of key mitochondrial metabolic proteins.
• DIPGs with PIK3CA mutations exhibit heightened sensitivity to ONC201.
• TP53 mutations are associated with ONC201 resistance.
• PI3K/Akt signaling mediates metabolic adaptation, conferring resistance to ONC201, which can be reversed by paxalisib.

Conclusions:

• ONC201 effectively targets mitochondrial homeostasis in DIPG via ClpP agonism.
• Genomic context, particularly PIK3CA and TP53 mutations, significantly influences ONC201 response.
• Combination therapy with ONC201 and PI3K/Akt inhibitors like paxalisib presents a promising strategy for treating DIPG/DMG.