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

in Cancer discovery by Sriram Venneti, Abed Rahman Kawakibi, Sunjong Ji, Sebastian M Waszak, Stefan R Sweha, Mateus Mota, Matthew Pun, Akash Deogharkar, Chan Chung, Rohinton S Tarapore, Samuel Ramage, Andrew Chi, Patrick Y Wen, Isabel Arrillaga-Romany, Tracy T Batchelor, Nicholas A Butowski, Ashley Sumrall, Nicole Shonka, Rebecca A Harrison, John de Groot, Minesh Mehta, Matthew D Hall, Doured Daghistani, Timothy F Cloughesy, Benjamin M Ellingson, Kevin Beccaria, Pascale Varlet, Michelle M Kim, Yoshie Umemura, Hugh Garton, Andrea Franson, Jonathan Schwartz, Rajan Jain, Maureen Kachman, Heidi Baum, Charles F Burant, Sophie L Mottl, Rodrigo T Cartaxo, Vishal John, Dana Messinger, Tingting Qin, Erik Peterson, Peter Sajjakulnukit, Karthik Ravi, Alyssa Waugh, Dustin Walling, Yujie Ding, Ziyun Xia, Anna Schwendeman, Debra Hawes, Fusheng Yang, Alexander R Judkins, Daniel Wahl, Costas A Lyssiotis, Daniel de la Nava, Marta M Alonso, Augustine Eze, Jasper Spitzer, Susanne V Schmidt, Ryan J Duchatel, Matthew D Dun, Jason E Cain, Li Jiang, Sylwia A Stopka, Gerard Baquer, Michael S Regan, Mariella G Filbin, Nathalie Y R Agar, Lili Zhao, Chandan Kumar-Sinha, Rajen Mody, Arul Chinnaiyan, Ryo Kurokawa, Drew Pratt, Viveka N Yadav, Jacques Grill, Cassie Kline, Sabine Mueller, Adam Resnick, Javad Nazarian, Joshua E Allen, Yazmin Odia, Sharon L Gardner, Carl Koschmann

TLDR

  • The study found that ONC201 is effective in treating a type of brain tumor called H3K27M-mutant diffuse midline glioma (DMG). The study also figured out how ONC201 works to treat the tumor. The study supports ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. The study also identified the mechanism behind the efficacy of ONC201 in H3K27M-mutant DMG, which could inform future research and clinical practice. However, the study has some limitations, such as a small sample size, and more research is needed to validate the findings in a larger population. Future research could also explore the combination of ONC201 with other therapies for H3K27M-mutant DMG.

Abstract

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Overview

  • The study assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies of ONC201 for H3K27M-mutant diffuse midline glioma (DMG).
  • The primary objective of the study was to determine the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. The study also aimed to identify the mechanism behind the efficacy of ONC201 in H3K27M-mutant DMG.

Comparative Analysis & Findings

  • Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes.

Implications and Future Directions

  • The study demonstrates the efficacy of ONC201 in H3K27M-mutant DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. The findings support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. The study also identifies the mechanism behind the efficacy of ONC201 in H3K27M-mutant DMG, which could inform future research and clinical practice. Limitations of the study include the small sample size and the need for further research to validate the findings in a larger population. Future research could also explore the combination of ONC201 with other therapies for H3K27M-mutant DMG.
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