Functional Drug Screening of Small Molecule Inhibitors of Epigenetic Modifiers in Refractory AML Patients

Jessica L Dennison; Hassan Al-Ali; Claude-Henry Volmar; Shaun Brothers; Justin Watts; Claes Wahlestedt; Ines Lohse

doi:10.3390/cancers14174094

Functional Drug Screening of Small Molecule Inhibitors of Epigenetic Modifiers in Refractory AML Patients

Cancers (Basel). 2022 Aug 24;14(17):4094. doi: 10.3390/cancers14174094.

Authors

Jessica L Dennison^{1

2}, Hassan Al-Ali^{3

4}, Claude-Henry Volmar^{1

2

5}, Shaun Brothers^{1

2

5}, Justin Watts⁶, Claes Wahlestedt^{1

2}, Ines Lohse^{1

2

5}

Affiliations

¹ Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
² Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
³ Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
⁴ Peggy and Harold Katz Family Drug Discovery Center, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
⁵ Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
⁶ Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.

Abstract

The use of inhibitors of epigenetic modifiers in the treatment of acute myeloid leukemia (AML) has become increasingly appealing due to the highly epigenetic nature of the disease. We evaluated a library of 164 epigenetic compounds in a cohort of 9 heterogeneous AML patients using an ex vivo drug screen. AML blasts were isolated from bone marrow biopsies according to established protocols and treatment response to the epigenetic library was evaluated. We find that 11 histone deacetylase (HDAC) inhibitors, which act upon mechanisms of cell cycle arrest and apoptotic pathways through inhibition of zinc-dependent classes of HDACs, showed efficacy in all patient-derived samples. Other compounds, including bromodomain and extraterminal domain (BET) protein inhibitors, showed efficacy in most samples. Specifically, HDAC inhibitors are already clinically available and can be repurposed for use in AML. Results in this cohort of AML patient-derived samples reveal several epigenetic compounds with high anti-blast activity in all samples, despite the molecular diversity of the disease. These results further enforce the notion that AML is a predominantly epigenetic disease and that similar epigenetic mechanisms may underlie disease development and progression in all patients, despite differences in genetic mutations.

Keywords: AML; BET inhibitors; HDAC inhibitors; drug screening; epigenetics; histone modifiers.

Grants and funding

This work was supported by the University of Miami Sylvester Comprehensive Cancer Center Molecular Therapeutics Shared Resource (MTSR) and the Sylvester Comprehensive Cancer Center Support Grant, 1P30CA240139-01. S.B. received support from the National Institutes of Health (P30CA240139, R01NS092671, R01MH110441). I.L. is supported through grants from the Hyundai Hope on Wheels foundation, the Sebastian Strong foundation, and the Woman’s Cancer Association of the University of Miami. C.W.’s laboratory is currently publicly funded by NIH grants DA035592, DA035055, and AA023781, Florida Department of Health grants 6AZ08, 7AZ26, and 21L01, and the Wallace H. Coulter foundation.