Abstract 4031: Mutant isocitrate dehydrogenase 1 (IDH1) inhibitor synergistically prolongs animal survival with standard therapies in patient-derived IDH1 mutant glioma xenograft mouse models

Abstract

Abstract Background: Mutation in isocitrate dehydrogenase 1 (IDH1) occurs in > 70% of WHO grades II and III astrocytomas and oligodendrogliomas and secondary glioblastoma (GBM). The mutant enzyme catalyze the reduction of α-ketoglutaric acid to D-2-hydroxyglutaric acid, leading to cancer initiation. In this study, we examined the therapeutic efficacy of SYC-435 (1-hydroxypyridin-2-one), a newly developed mutant IDH1inhibitor, both in vitro and in vivo in IDH1 mutant gliomas as compared with IDH1 wild type GBMs. Methods: An established neurosphere line (BT142) of anaplastic oligoastrocytoma (AOA), and a patient-derived orthotopic xenograft (PDOX) model of recurrent AOA (IC-V0914AOA), and 2 PDOX models of GBM (IC-4687GBM and IC-3752GBM) were included. IDH1 mutations (R132H and R132C) were analyzed by pyrosequencing. To determine the in vitro antitumor activities, tumor cells were exposed to SYC-435 (0.02 to 20 µM) and examining for changes of cell proliferation every 3-4 days till day 13 by Cell Counting Kit-8 assay. For in vivo effects, orthotopic xenograft mouse models of IC-BT142AOA and IC-V0914AOA were treated with vehicle (as control), SYC-435 (i.p., 15 mg/kg/day x 28 days), temozolomide (TMZ, oral, 50 mg/kg/day x 5 days) + fractionated radiation (XRT, 2 Gy/day x 5 days) (as standard therapy), and combination of SYC-435 with standard therapy starting 2 weeks after intracranial tumor implantation. Animal survival times were analyzed by log rank analysis. Results: IDH1 R132H mutation (homozygous) was detected in BT142AOA neurosphere line and R132C mutation (mutant allele frequency 39-42%) in IC-V0914AOA xenograft cells, while the two GBM models (IC-4687GBM and IC-3752GBM) carried wild-type IDH1. Suppression of cell growth was observed in time- and dose-dependent manner by SYC-435, particularly at the IDH1 mutant models. At 0.5 µM, SYC-435 inhibited cell growth by 90% in BT142 and 60% in IC-V0914AOA cells, whereas in IDH wild-type GBMs only by 17% in IC-4687GBM and 19% in IC-3752GBM cells at day 13, indicating the high selectivity of SYC-435 of mutant over wild type IDH1. Systematic in vivo treatment with SYC-435 alone did not alter survival times in neither IC-BT142AOA nor IC-V0914AOA models when compared with the control group. Although standard therapy significantly prolonged animal survival times in both models (P<0.0005), combining SYC-435 with standard therapies further extended the median survival times from 106 days (in the standard therapy group) to 124 days (P<0.05) in IC-V0914AOA and exhibited similar trend in IC-BT142AOA. Conclusion: SYC-435 possesses antitumor effects that are highly selective in IDH1 mutant gliomas, and generated strong synergistic activities with standard therapies in vivo. Our data support the clinical testing of SYC-435 in patients with IDH1 mutant glioma. Citation Format: Mari Kogiso, Lin Qi, Huiyuan Zhang, Frank K. Braun, Yuchen Du, Yulun Huang, Holly Lindsay, Sibo Zhao, Sarah G. G. Injac, Zhen Liu, Patricia A. Baxter, Jack M. Su, Laszlo Perlaky, D. Williams Parsons, Murali Chintagumpala, Adekunle Adesina, Jialiang Wang, Yongcheng Song, Xiao-Nan Li. Mutant isocitrate dehydrogenase 1 (IDH1) inhibitor synergistically prolongs animal survival with standard therapies in patient-derived IDH1 mutant glioma xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4031. doi:10.1158/1538-7445.AM2017-4031