Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft

Abstract

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin–ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin–ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

Prioritization of Osteoporosis‐Associated Genome‐wide Association Study (GWAS) Single‐Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics

“…( 72 ) Besides a role for HMGA2 in negatively regulating MSC differentiation to ostb, it may play a protective role in the skeleton ( 74 ) at later steps in differentiation of ostb to osteocytes and in osteocyte homeostasis by helping to induce autophagy. ( 71,75,76 )…”

Targeting EZH2 for the treatment of soft tissue sarcomas

“…Of 62 treated participants, with a median of 1 prior therapy, 15% exhibited partial responses with objective response rate and disease control rate of 15% and 26%, respectively. The duration of response to the treatment ranged from 7.1 to 103.0 weeks and a median overall survival of 82.4 weeks was observed for all 62 patients [60] .…”

“…A study involving patient-derived INI1-negative ES tumour samples xenotransplanted to immunodeficient mice and administration of EPZ011989 resulted in tumour growth stabilization at first, followed by tumour volume inhibition of up to 89% and decreased H3K27me3 [60,61] . A clinical trial of patients with SMARCB1(INI1)-negative ES treated with tazemetostat showed similar results to SS patients.…”

Current Approaches for Personalized Therapy of Soft Tissue Sarcomas

“…ere are a number of studies based on patient-derived cells (PDC) and patient-derived xenograft (PDX) model in vivo. However, most of the described investigations are focused on establishment of new cell line derived from patient tumor (for example, see [63][64][65][66][67], on preclinical studies of novel or repurposed drug/combination of drugs in vitro [68][69][70][71] and in vivo [72][73][74]). Only a few studies address the optimization of STS treatment.…”