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Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.
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.
  • Konopleva M; The University of Texas, MD Anderson Cancer Center.
  • DiNardo C; UT MD Anderson Cancer Center.
  • Bhagat T; Albert Einstein College of Medicine.
  • Baran N; The University of Texas MD Anderson Cancer Center.
  • Lodi A; College of Natural Sciences, The University of Texas at Austin.
  • Saxena K; The University of Texas, MD Anderson Cancer Center.
  • Cai T; The University of Texas, MD Anderson Cancer Center.
  • Su X; Dan L. Duncan Cancer Center and , Baylor College of Medicine.
  • Skwarska A; Albert Einstein College of Medicine-Montefiore Medical Center.
  • Guerra V; MD Anderson Cancer Center.
  • Kuruvilla V; The University of Texas, MD Anderson Cancer Center.
  • Konoplev S; MD Anderson cancer Center, The University of Texas.
  • Gordon-Mitchell S; Albert Einstein College of Medicine.
  • Pradhan K; Albert Einstein College of Medicine.
  • Aluri S; Albert Einstein College of Medicine.
  • Collins M; College of Natural Sciences, The University of Texas at Austin.
  • Sweeney S; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
  • Busquet J; Dell Medical School, The University of Texas at Austin.
  • Rathore A; Dell Medical School, The University of Texas at Austin.
  • Deng Q; The University of Texas MD Anderson Cancer Cent.
  • Green M; MD Anderson Cancer Centre.
  • Grant S; Department of Medicine, Virginia Commonwealth University.
  • Demo S; Calithera Biosciences.
  • Choudhary G; Albert Einstein College of Medicine-Montefiore Medical Center.
  • Sahu S; Albert Einstein College of Medicine.
  • Agarwal B; GenomeRxUs LLC.
  • Spodek M; Albert Einstein College of Medicine-Montefiore Medical Center.
  • Thiruthuvanathan V; Albert Einstein College of Medicine.
  • Will B; Albert Einstein College of Medicine.
  • Steidl U; Albert Einstein College of Medicine.
  • Tippett G; The University of Texas, MD Anderson Cancer Center.
  • Burger J; MD Anderson Cancer Center.
  • Borthakur G; The University of Texas MD Anderson Cancer Center.
  • Jabbour E; The University of Texas MD Anderson Cancer Center.
  • Pemmaraju N; The University of Texas, MD Anderson Cancer Center.
  • Kadia T; The University of Texas MD Anderson Cancer Center.
  • Komblau S; The University of Texas MD Anderson Cancer Center.
  • Daver N; The University of Texas MD Anderson Cancer Center.
  • Naqvi K; The University of Texas, MD Anderson Cancer Center.
  • Short N; The University of Texas, MD Anderson Cancer Center.
  • Garcia-Manero G; MD Anderson Cancer Center.
  • Tiziani S; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
  • Verma A; Montefiore Einstein Cancer Center.
Res Sq ; 2023 Feb 23.
Article en En | MEDLINE | ID: mdl-36865338
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.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2023 Tipo del documento: Article