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GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas
Abstract:
Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction and have emerged as promising therapies for DMG patients. However, efficacy as monotherapy is limited, identifying a need for strategies that enhance response. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment onset. Here, using 1 H-magnetic resonance spectroscopy, which is a non-invasive method of quantifying metabolite pool sizes, we show that accumulation of ψ-aminobutyric acid (GABA) is an early metabolic biomarker that can be detected within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic xenografts. Mechanistically, imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, which synthesizes GABA, and downregulates ABAT , which degrades GABA, leading to GABA accumulation in DMG cells and tumors. Functionally, GABA secreted by imipridone-treated cells acts in an autocrine manner via the GABAB receptor to induce expression of superoxide dismutase (SOD1), which mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking autocrine GABA signaling using the clinical stage GABAB receptor antagonist SGS-742 exacerbates oxidative stress and synergistically induces apoptosis in combination with imipridones in DMG cells and orthotopic tumor xenografts. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for non-invasive assessment of drug-target engagement and therapy. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for DMG patients.
One Sentence Summary:
Imipridones induce GABA accumulation in diffuse midline gliomas, an effect that can be leveraged for therapy and non-invasive imaging.
Insights
Imipridone drugs increase GABA in pediatric brain tumors, acting as an early biomarker for treatment response. This metabolic adaptation can be targeted to enhance therapy and enable non-invasive imaging for diffuse midline gliomas.
Area of Science:
- Neuro-oncology
- Metabolic imaging
- Drug discovery
Background:
- Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with limited treatment options.
- Imipridones show promise but require strategies to improve efficacy and early response monitoring.
- Biomarkers for early drug-target engagement are crucial for optimizing DMG treatment.
Purpose of the Study:
- To identify early metabolic biomarkers for imipridone therapy in DMGs.
- To elucidate the mechanism of imipridone-induced metabolic changes.
- To explore the therapeutic potential of targeting this metabolic adaptation.
Main Methods:
- Utilized 1H-magnetic resonance spectroscopy for non-invasive metabolite quantification in preclinical DMG models.
- Investigated the molecular pathways involving ClpP, ATF4, and GABA synthesis/degradation.
- Assessed the functional role of GABA signaling via GABAB receptors and its impact on oxidative stress.
Main Results:
- Accumulation of gamma-aminobutyric acid (GABA) detected within one week of ONC206 treatment, serving as an early biomarker.
- Imipridones activate ClpP and ATF4, leading to increased GABA synthesis and decreased degradation.
- Autocrine GABA signaling via GABAB receptors induces SOD1, mitigating oxidative stress; blocking this signaling synergizes with imipridones to induce apoptosis.
Conclusions:
- GABA accumulation is an early metabolic adaptation to imipridones in DMGs, useful for non-invasive imaging and assessing drug-target engagement.
- Targeting GABA signaling pathways, in combination with imipridones, offers a potential strategy for enhanced DMG therapy.
- This work paves the way for precision metabolic therapy and imaging in pediatric brain tumor patients.
