Demonstrated Efficacy and Mechanisms of Sensitivity of ONC201 in H3K27M-Mutant Diffuse Midline Glioma

Review of Two New Studies on ONC201 Treatment for H3K27M-Mutant Diffuse Midline Glioma (H3K27M-DMG)

This review reports on two new studies investigating the small molecule compound ONC201 for the treatment of H3K27M-mutant diffuse midline glioma (H3K27M-DMG).

Background: H3K27M-DMG is an aggressive primary brain tumor that predominantly affects children and young adults. These tumors are located in the midline region and are characterized by a mutation at the 27th amino acid of histone H3.1 or H3.3. The current standard of care is radiation therapy, but no effective systemic therapy is available. ONC201 is a novel small molecule initially discovered to activate the TRAIL apoptosis pathway. Subsequently, it was found to target the mitochondrial protease ClpP, leading to its over-activation and mitochondrial protein degradation. In a phase 2 study of unselected glioblastoma, researchers unexpectedly found that only patients with H3K27M mutations responded to ONC201.

Study 1 (Source: Cancer Discovery, Venneti et al.): This study reported overall survival data for newly diagnosed H3K27M-DMG patients treated with ONC201. A total of 35 patients were enrolled, and the median overall survival was 21.7 months, significantly higher than historical controls (12 months). When stratified by tumor location, patients with brainstem and thalamic tumors showed significantly prolonged survival compared to controls. Mechanistic studies revealed that ONC201 inhibited the tricarboxylic acid cycle, promoting glutamine metabolism to produce L-2-hydroxyglutarate (L-2HG), an inhibitor of histone demethylases. Post-treatment tumor and cerebrospinal fluid samples showed increased L-2HG levels, accompanied by increased H3K27 trimethylation, potentially reversing the epigenetic changes caused by the H3K27M mutation.

Study 2 (Source: Journal of Clinical Oncology, Arrillaga-Romany et al.): This study analyzed the efficacy of ONC201 monotherapy in 50 recurrent H3K27M-DMG patients across 5 clinical trials. Per RANO criteria, the objective response rate was 20%, and the disease control rate was 40%. According to low-grade glioma RANO criteria, the response rate was 26%, and the disease control rate was 42%. The median overall survival was 13.7 months. ONC201 demonstrated durable responses, with a median response duration of 8.3 months, a median duration of response of 11.2 months, and an overall favorable safety profile.

Summary: These two studies elucidate the significant efficacy of ONC201 in H3K27M-DMG patients and provide insights into a potential mechanism – reversing the epigenetic changes caused by the H3K27M mutation through metabolic reprogramming. This offers a promising targeted therapy for H3K27M-DMG, and a phase 3 global action study is currently ongoing to further validate the efficacy of ONC201.