H3 K27M-mutant Diffuse Glioma Research Articles

Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas.

e14037 Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.

DIPG-62. PRECLINICAL EVALUATION OF IMIPRIDONE-BASED COMBINATION THERAPIES IN PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Imipridones induce apoptosis in cancer via p53 independent upregulation of TNF-related apoptosis inducing ligand (TRAIL) pathway and its proapoptotic receptor DR5. ONC201, a first-in-class imipridone, is being evaluated alone and with radiotherapy for children with H3K27M mutant diffuse glioma. We sought to determine if ONC201 and its imipridone analogs (ONC206, ONC212) are synergistic with other chemotherapy agents. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SU-DIPG-27, SU-DIPG-29, SF8628) and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to ONC201, ONC206, and ONC212 alone and in combination with histone de-acetylase inhibitors (HDACi) or etoposide. A dose-dependent response to ONC201, ONC206, and ONC212 was demonstrated in all cell lines, with mean IC50 values of 1.46 µM, 0.11 µM, and 0.03 µM respectively. ONC206 and ONC212 induced apoptosis measured by increased expression of cleaved PARP and ISR by increased expression ATF4. In two cell lines, synergy studies revealed combination indices (CI) < 1 for ONC206 and etoposide, with a best CI of 0.62 in SU-DIPG-IV and 0.46 in SU-DIPG-25. Synergy was also observed between ONC201 and etoposide (CI 0.46) and ONC201 and panobinostat (CI 0.01). Imipridones and analogs were superior to panobinostat and etoposide in triggering apoptosis as measured by sub-G1 phase content. Additional synergy and mechanistic analyses are ongoing and will be reported. Our results suggest that H3K27M mutant DIPG cells demonstrate increased sensitivity to imipridone analogs (ONC206 and ONC212) when compared to ONC201. Combinational strategies with etoposide or HDACi should be considered for clinical translation.