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A Brain Penetrant Mutant IDH1 Inhibitor Provides In Vivo Survival Benefit
Johnny Kopinja1, Raquel S Sevilla1, Diane Levitan1
1Merck & Co., Inc., Merck Research Laboratories, Kenilworth, NJ, 07033, USA.
Abstract:
Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.
Insights
Targeting isocitrate dehydrogenase 1 (IDH1) mutations in glioma with selective inhibitors reduced 2-hydroxyglutarate (2-HG) and improved survival in patient models, suggesting a new therapeutic avenue.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Drug Discovery
Background:
- Isocitrate dehydrogenase 1 (IDH1) mutations are common in human glioma.
- Current radiotherapy treatments for glioma can cause significant morbidities.
- There is a need for alternative, brain-penetrant therapies targeting IDH1 mutations.
Purpose of the Study:
- To evaluate the therapeutic potential of IDH1 mutant-selective inhibitors.
- To assess the impact of intracranial 2-hydroxyglutarate (2-HG) inhibition in IDH1 mutant glioma models.
Main Methods:
- Utilized IDH1 mutant patient-derived glioma cell line models.
- Administered IDH1 mutant-selective inhibitors.
- Measured intracellular 2-HG levels in vitro and in vivo.
- Assessed glioma cell proliferation and animal survival.
Main Results:
- Inhibitor treatment decreased intracellular 2-HG levels in IDH1 mutant models.
- In vitro cell proliferation was unaffected by 2-HG inhibition.
- Significant survival benefits were observed in vivo with IDH1 mutant-selective inhibitors.
- Not all IDH1 mutant glioma models responded to treatment despite near-complete 2-HG inhibition.
Conclusions:
- Brain-penetrant IDH1 mutant-selective inhibitors can reduce 2-HG levels in glioma.
- Disrupting 2-HG production offers potential survival benefits for IDH1 mutant glioma patients.
- Further research is needed to understand differential treatment responses.
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