Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.

Autor:	Tayari MM; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida., Santos HGD; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida., Kwon D; Sylvester Comprehensive Cancer Center, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida., Bradley TJ; Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida., Thomassen A; Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida., Chen C; Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida., Dinh Y; Department of Immuno-Oncology, Oncology Division, IQVIA Biotech, Miami, Florida., Perez A; Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida., Zelent A; Department of Molecular Biology, Institute of Genetics and Animal Biotechnology PAS, Warsaw, Poland., Morey L; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida., Cimmino L; Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida., Shiekhattar R; Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida., Swords RT; Medical Director, AbbVie Pharmaceuticals, Chicago, Illinois., Watts JM; Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. jxw401@miami.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Apr 01; Vol. 27 (7), pp. 1893-1903. Date of Electronic Publication: 2021 Jan 25.
DOI:	10.1158/1078-0432.CCR-20-4054
Abstrakt:	Purpose: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Patients and Methods: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). Results: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34 + cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34 + phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. Conclusions: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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