A high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML.

Autor: Drenberg CD; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA. guttke.1@osu.edu.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. guttke.1@osu.edu., Shelat A; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Dang J; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Cotton A; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Orwick SJ; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Li M; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Jeon JY; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Fu Q; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Buelow DR; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Pioso M; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Hu S; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Inaba H; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Ribeiro RC; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Rubnitz JE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Gruber TA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA., Guy RK; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40506, USA., Baker SD; Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.; Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 May 16; Vol. 10 (1), pp. 2189. Date of Electronic Publication: 2019 May 16.
DOI: 10.1038/s41467-019-09917-0
Abstrakt: Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates <40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.
Databáze: MEDLINE
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