Journal Article

Small molecule inhibition of lysine-specific demethylase 1 (LSD1) and histone deacetylase (HDAC) alone and in combination in Ewing sarcoma cell lines

Cubitt, Christopher L., Kahen, Elliot, Reed, Damon R., Welch, Darcy, Brohl, Andrew S., Fridley, Brooke

2019

Overview

Ewing Sarcoma (ES) is characterized by recurrent translocations between EWSR1 and members of the ETS family of transcription factors. The transcriptional activity of the fusion oncoprotein is dependent on interaction with the nucleosome remodeling and deactylase (NuRD) co-repressor complex. While inhibitors of both histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1) subunits of the NuRD complex demonstrate single agent activity in preclinical models, combination strategies have not been investigated. We selected 7 clinically utilized chemotherapy agents, or active metabolites thereof, for experimentation: doxorubicin, cyclophosphamide, vincristine, etoposide and irinotecan as well as the HDAC inhibitor romidepsin and the reversible LSD1 inhibitor SP2509. All agents were tested at clinically achievable concentrations in 4 ES cell lines. All possible 2 drug combinations were then tested for potential synergy. Order of addition of second-line conventional combination therapy agents was tested with the addition of SP2509. In two drug experiments, synergy was observed with several combinations, including when SP2509 was paired with topoisomerase inhibitors or romidepsin. Addition of SP2509 after treatment with second-line combination therapy agents enhanced treatment effect. Our findings suggest promising combination treatment strategies that utilize epigenetic agents in ES.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antineoplastic Agents - administration & dosage / Antineoplastic Agents - therapeutic use / Biotechnology / Bone cancer / Bone Neoplasms - drug therapy / Bone Neoplasms - enzymology / Cancer therapies / Cell cycle / Cell Line, Tumor / Chemotherapy / Clinical trials / Cyclophosphamide / Cyclophosphamide - administration & dosage / Cyclophosphamide - therapeutic use / Depsipeptides - administration & dosage / Depsipeptides - therapeutic use / Doxorubicin / Doxorubicin - administration & dosage / Doxorubicin - therapeutic use / Drug Synergism / Drug Therapy, Combination - methods / Epigenetics / Etoposide / Etoposide - administration & dosage / Etoposide - therapeutic use / Ewing's sarcoma / Ewings sarcoma / Experimentation / FLI-1 protein / Histone deacetylase / Histone Deacetylase Inhibitors - administration & dosage / Histone Deacetylase Inhibitors - therapeutic use / Histone Deacetylases - drug effects / Histone Deacetylases - metabolism / Histone Demethylases - antagonists & inhibitors / Histones / Humans / Hydrazines - administration & dosage / Hydrazines - therapeutic use / Inhibitors / Irinotecan / Irinotecan - administration & dosage / Irinotecan - therapeutic use / Lysine / Medical research / Medicine and Health Sciences / Metabolites / NuRD protein / Pediatrics / Prostate cancer / Reagents / Research and Analysis Methods / Sarcoma / Sarcoma, Ewing - drug therapy / Sarcoma, Ewing - enzymology / Sulfonamides - administration & dosage / Sulfonamides - therapeutic use / Teenagers / Transcription factors / Translocation / Tumor cell lines / Vincristine / Vincristine - administration & dosage / Vincristine - therapeutic use / Young adults