Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses-Reference-Cited by-同舟云学术

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

Published:2023-02-23 Issue: Volume: Page:
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Author:

Konopleva Marina¹,DiNardo Courtney²^ORCID,Bhagat Tushar³,Baran Natalia⁴^ORCID,Lodi Alessia⁵,Saxena Kapil¹,Cai Tianyu¹,Su Xiaoping⁶,Skwarska Anna⁷,Guerra Veronica⁸,Kuruvilla Vinitha¹,Konoplev Sergej⁹,Gordon-Mitchell Shanisha³,Pradhan Kith³,Aluri Srinivas³,Collins Meghan⁵^ORCID,Sweeney Shannon¹⁰,Busquet Jonathan¹¹,Rathore Atul¹¹,Deng Qing¹²,Green Michael¹³^ORCID,Grant Steven¹⁴,Demo Susan¹⁵,Choudhary Gaurav⁷,Sahu Srabani³,Agarwal Beamon¹⁶,Spodek Mason⁷,Thiruthuvanathan Victor³,Will Britta³,Steidl Ulrich³,Tippett George¹,Burger Jan⁸,Borthakur Gautam⁴^ORCID,Jabbour Elias⁴,Pemmaraju Naveen¹,Kadia Tapan⁴,Kornblau Steven⁴^ORCID,Daver Naval⁴^ORCID,Naqvi Kiran¹,Short Nicholas¹,Garcia-Manero Guillermo⁸^ORCID,Tiziani Stefano¹⁰,Verma Amit¹⁷

Affiliation:

1. The University of Texas, MD Anderson Cancer Center

2. UT MD Anderson Cancer Center

3. Albert Einstein College of Medicine

4. The University of Texas MD Anderson Cancer Center

5. College of Natural Sciences, The University of Texas at Austin

6. Dan L. Duncan Cancer Center and , Baylor College of Medicine

7. Albert Einstein College of Medicine-Montefiore Medical Center

8. MD Anderson Cancer Center

9. MD Anderson cancer Center, The University of Texas

10. Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA

11. Dell Medical School, The University of Texas at Austin

12. The University of Texas MD Anderson Cancer Cent

13. MD Anderson Cancer Centre

14. Department of Medicine, Virginia Commonwealth University

15. Calithera Biosciences

16. GenomeRxUs LLC

17. Montefiore Einstein Cancer Center

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

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