Metabolomics data: glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes

Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of Telaglenastat (CB-839), a selective GLS inhibitor, when combined with AZA, in vitro and in vivo, followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with Telaglenastat/AZA led to an ORR of 70% with CRs in 66% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells and was associated with clinical responses to Telaglenastat/AZA; was predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.