P1, N=36, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2026 --> Feb 2027 | Trial primary completion date: Feb 2026 --> Feb 2027

P2, N=93, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1/2, N=130, Active, not recruiting, Celgene | Trial completion date: Sep 2025 --> Sep 2026

P2/3, N=247, Recruiting, Europese Organisatie Voor Onderzoek En Behandeling Van Kanker Organisation Europeenne Pour La Recherche Et Le Traitement Du Cancer European Organi

A panel of human and murine breast cancer cell lines was treated with the IDH2 inhibitor AGI-6780, alone or in combination with the proteasome inhibitor carfilzomib (CFZ) or the E1 ubiquitin-activating enzyme inhibitor TAK-243. Inhibition of IDH2 markedly enhances the cytotoxic effects of proteasome-targeting by disrupting metabolic-proteostatic balance and promoting apoptotic cell death. These findings identify a growth-inhibitory effect that may be leveraged to improve functional dependency in breast cancer, particularly in triple-negative breast cancer, which currently lacks efficient drug treatments.

In addition, treatments with the IDH-mutant inhibitors vorasidenib and ivosidenib further sensitize the cells to ferroptosis. Furthermore, dietary cysteine-methionine deprivation alone or in combination with convection-enhanced delivery of RSL3 or ivosidenib in vivo significantly prolongs survival of IDH1-mutant tumor-bearing mice. Our findings suggest that targeting cysteine and methionine metabolism in combination with IDH-mutant inhibition provides promising therapeutic strategies for IDH1-mutant gliomas.

P2, N=15, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2027 --> Feb 2029 | Trial primary completion date: May 2027 --> Jan 2028

P3, N=468, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

These results highlight the potential of ¹⁸F-DOPA-PET and advanced MRI sequences as valuable complements to standard RANO 2.0 MRI evaluations for assessing treatment response in glioma patients undergoing IDHi therapy.

P1, N=4, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Oct 2026 --> Jan 2026 | Trial primary completion date: Oct 2026 --> Jan 2026

Using these models, we tracked clonal evolution under selective pressure from IDH inhibitors and combination therapies, identifying an association between WT1 mutations and ivosidenib (IDH1 inhibitor) monotherapy resistance, as well as an antagonism between ivosidenib and enasidenib (IDH2 inhibitor) when tested in IDH1-mutated cells. Our findings demonstrate how single-cell proteogenomic analysis of PDX models can illuminate drug resistance mechanisms and inform therapeutic strategies.

Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.