Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses

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...

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Detalles Bibliográficos
Autores principales: Konopleva, Marina, DiNardo, Courtney, Bhagat, Tushar, Baran, Natalia, Lodi, Alessia, Saxena, Kapil, Cai, Tianyu, Su, Xiaoping, Skwarska, Anna, Guerra, Veronica, Kuruvilla, Vinitha, Konoplev, Sergej, Gordon-Mitchell, Shanisha, Pradhan, Kith, Aluri, Srinivas, Collins, Meghan, Sweeney, Shannon, Busquet, Jonathan, Rathore, Atul, Deng, Qing, Green, Michael, Grant, Steven, Demo, Susan, Choudhary, Gaurav, Sahu, Srabani, Agarwal, Beamon, Spodek, Mason, Thiruthuvanathan, Victor, Will, Britta, Steidl, Ulrich, Tippett, George, Burger, Jan, Borthakur, Gautam, Jabbour, Elias, Pemmaraju, Naveen, Kadia, Tapan, Komblau, Steven, Daver, Naval, Naqvi, Kiran, Short, Nicholas, Garcia-Manero, Guillermo, Tiziani, Stefano, Verma, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980221/
https://www.ncbi.nlm.nih.gov/pubmed/36865338
http://dx.doi.org/10.21203/rs.3.rs-2518774/v1
Descripción
Sumario: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 azacytidine (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 CR/mCRs in 53% 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; was associated with clinical responses to telaglenastat/AZA and 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.

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