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

Nat Commun. 2019 May 16;10(1):2189. doi: 10.1038/s41467-019-09917-0.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bone Marrow / pathology
  • Bone Marrow / radiation effects
  • Bone Marrow Transplantation
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Cytarabine / pharmacology
  • Cytarabine / therapeutic use
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Disease-Free Survival
  • Female
  • Gemcitabine
  • High-Throughput Screening Assays / methods
  • Humans
  • Infant
  • Janus Kinase Inhibitors / pharmacology*
  • Janus Kinase Inhibitors / therapeutic use
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Experimental / etiology
  • Leukemia, Experimental / mortality
  • Leukemia, Experimental / pathology
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Taxoids / pharmacology
  • Taxoids / therapeutic use
  • Whole-Body Irradiation / adverse effects
  • Xenograft Model Antitumor Assays
  • Young Adult

Substances

  • Janus Kinase Inhibitors
  • Taxoids
  • Cytarabine
  • Deoxycytidine
  • cabazitaxel
  • Gemcitabine