Journal Article

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies

Zhang, Huiyuan, Earley, Eric J., Qi, Lin, Guo, Lei, Kogiso, Mari, Erickson, Stephen W., Du, Yuchen, Injac, Sarah G., Xiao, Sophie, Baxter, Patricia A., Su, Jack MF, Lindsay, Holly, Braun, Frank K., Zhao, Sibo, Teicher, Beverly, Li, Xiao-Nan, Smith, Malcolm A.

2022

Overview

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one [IC-1078MB (group 4)] showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets. This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.

• Publisher: Elsevier Inc,Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/51 / 38/39 / 45/41 / 631/154/436 / 631/67 / 64/60 / Adolescent / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Benzamides - administration & dosage / Benzamides - pharmacology / Biphenyl Compounds - administration & dosage / Biphenyl Compounds - pharmacology / Brain / Brain cancer / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - therapy / Brain tumors / Cell culture / Chemoradiotherapy / Child / Cisplatin / Cisplatin - administration & dosage / Combined Modality Therapy - methods / Drug Evaluation, Preclinical / Drug resistance / Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors / Enhancer of Zeste Homolog 2 Protein - genetics / Enhancer of Zeste Homolog 2 Protein - metabolism / Enzyme Inhibitors - administration & dosage / Enzyme Inhibitors - pharmacology / Evaluation / Female / Gene expression / Gene Expression Profiling - methods / Homology / Humans / Infant / Inhibitors / Laboratory Medicine / Male / Medicine / Medicine & Public Health / Medulloblastoma / Mice / Mice, Inbred NOD / Mice, SCID / Morpholines - administration & dosage / Morpholines - pharmacology / mRNA / Overexpression / Pathology / Patients / Pediatrics / Prolongation / Pyridones - administration & dosage / Pyridones - pharmacology / Radiation / Radiation therapy / Radiotherapy Dosage / Statistical analysis / Survival / Therapeutic targets / Tumor cells / Tumors / Xenograft Model Antitumor Assays - methods / Xenografts / Xenotransplantation