Novel Insights into Using CRISPR-Mediated Modulation of Dopaminergic Signaling Pathways to Enhance the Therapeutic Efficacy of ONC201 in the Treatment of Diffuse Intrinsic Pontine Glioma (DIPG)

Abstract

Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating childhood brain cancers, with a median survival of less than one year and almost no long-term survivors. Classified as a subtype of diffuse midline glioma (DMG) and characterized by the H3K27M mutation, DIPG remains resistant to surgery and conventional chemotherapy due to its location in the brainstem and its highly adaptive biology. ONC201, a first-in-class imipridone, has shown positive early clinical results in children with H3K27M-mutant DIPG by blocking dopamine receptor D2 (DRD2), overactivating the mitochondrial protease ClpP, and triggering stress and apoptosis pathways in tumor cells. While newer imipridones like ONC206 and ONC212 appear even more potent in laboratory models, ONC201 has the strongest clinical track record to date, making it the most practical candidate for exploring combination strategies.

CRISPR-Cas9 gene editing could be used to boost ONC201’s effects by targeting the survival mechanisms DIPG cells rely on. Potential strategies include knocking out dopamine receptors like DRD2/3, shutting down integrated stress response regulators such as PERK and GCN2, and removing anti-apoptotic genes like BCL2L1, MCL1, and XIAP that block cell death. Other promising approaches include editing PDGFRA or AKT to weaken compensatory growth pathways, or targeting CLPX to intensify ONC201-induced mitochondrial collapse. These genetic edits could work together to prevent resistance, amplify stress signals, and push DIPG cells past the point of recovery.

Still, major challenges remain. Delivering CRISPR safely across the blood–brain barrier is a significant hurdle, and most studies so far are limited to cell culture or glioblastoma models rather than DIPG itself. This highlights the urgent need for DIPG-specific in vivo research before clinical translation is possible. This review brings together what is currently known about ONC201, CRISPR, and their potential synergy, outlining both the opportunities and obstacles in moving toward a more effective treatment strategy for this lethal pediatric cancer.