Amino acyl tRNA synthetase inhibitors is therapeutics for gliomas at sub nanomolar concentrations

Abstract

Glioblastoma is the most malignant and fatal of all primary brain tumors. Each year in the United States, about 22,000 cases of glioma are diagnosed and about 70% of these patients die. The current treatment modality options available for glioma patients are limited to temozolomide, radiation, and surgery. The poor outcome with these treatment options has necessitated the search for a better chemotherapeutic strategy to improve patient outcomes. In a previous study, a genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) screen in glioblastoma was performed under human type II topoisomerase (TOP2) poison selection and found that various aminoacyl tRNA synthetases (AARS) were the most enriched in our screen. This high expression of AARS was validated by western blot and the gliomas were treated with sub-nanomolar doses of AARS inhibitors. Our results showed that AARS inhibitor treatment effectively killed 75 to 90% of the tumors within 72 h and that this killing is independent of DNA damage repair machinery. Taken together, the findings suggest that application of AARS inhibitors might be curative for glioma, but more experimental in-vivo tests will be needed to validate this.