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Abstract #1929

GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas

Georgios Batsios1, Suresh Udutha1, Celine Taglang1, Anne Marie Gillespie1, Benison Lau2, Sunjong Ji2, Timothy Phoenix3, Sabine Mueller1, Sriram Venneti2, Carl Koschmann2, and Pavithra Viswanath1
1University of Caifornia, San Francisco, San Francisco, CA, United States, 2University of Michigan, Ann Arbor, MI, United States, 3University of Cincinnati, Cincinnati, OH, United States

Synopsis

Keywords: Probes & Targets, Pediatric, preclinical, 1H-MRS, diffuse midline glioma

Motivation: Diffuse midline glioma (DMG) are fatal brain tumors in children. The imipridones ONC201 and ONC206 have shown promise in DMG treatment, but efficacy is limited, and biomarkers of treatment response are lacking.

Goal(s): To determine whether imipridones induced 1H-MRS-detectable metabolic alterations in preclinical DMG models in vivo.

Approach: Usage of 1H-MRS and biochemical methods in patient-derived DMG cells and tumor xenografts.

Results: We show that an increase in 1H-MRS-detectable GABA is a unique biomarker of response to imipridones. Importantly, GABA induces autocrine GABA signaling via the GABAB receptor that can be exploited to enhance response to imipridones in vivo.

Impact: We have developed an integrated metabolic therapy and 1H-MRS-based imaging strategy for diffuse midline glioma patients. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for children battling this devastating form of brain cancer.

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