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

Abstract

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

Bridging the age gap: a review of molecularly informed treatments for glioma in adolescents and young adults

“…Paxalisib is a PI3K-inhibitor under clinical investigation, which has shown encouraging responses in adult patients with recurrent HGGs ( 76 , 77 ). Paxalisib is also being evaluated for safety and efficacy in HGGs, including DIPG/DMG in combination with ONC201 (NCT05009992) ( 78 , 79 ).…”

Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma

“…Imipridones are a distinct class of small molecule anti-cancer compounds (21). Their primary mechanism of action is to activate mitochondrial protease CLPP causing dysregulated proteolysis of mitochondrial OXPHOS effectors like SDHA, SDHB, NDUFA12, thereby reducing their cellular levels (22)(23)(24). The imipridone compound ONC201 has shown efficacy in several preclinical models of solid tumors and hematologic malignancies, and showed promising safety, pharmacokinetic and pharmacodynamic efficacy profiles in phase I/II trials involving more than 100 patients (22,25).…”

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

“…Recent work demonstrated an additional aspect of the mechanism of action of ONC201, in which direct binding to and activation of the mitochondrial caseinolytic protease P (CLPP) result in impaired respiratory function and mitochondrial toxicity in leukemia, breast cancer, and H3K27M-DMG cells ( 7–9 ). In these settings, ONC201 binding results in CLPP hyperactivation, increased PI3K/AKT signaling driven by generation reactive oxygen species secondary to mitochondrial degradation ( 10, 11 ), and induction of apoptosis by activation of the ISR ( 7, 9 ).…”