Search

Background: Ependymoma (EPN) is the third most common malignant pediatric brain tumor. Current standard therapy include maximally safe surgical resection followed by radiation and lead to a 5-year overall survival of 50-71%. Recent molecular subgrouping of EPN has identified one group, posterior fossa A (PFA), which accounts for 45% of all EPN cases, to have one of the worst prognosis and it is driven by epigenetic changes, suggesting targeting epigenetic changes in PFA EPN can potentially be effective. In this study, we examined the therapeutic efficacy of SYC-836, a novel LSD-1 inhibitor compound developed at Baylor College of Medicine, both in vitro and in vivo in PDOX models of posterior fossa EPN. Methods: To examine in vitro anti-tumor activities, paired primary cultured cells (both as attached cells and neurospheres) from an established PDOX model of posterior fossa EPN (ICb-4423EPN) were subjected to SYC-836 at various concentrations (0-25uM). Cell viability and proliferation were measured using Cell Counting Kit-8 assay at 5 different time points over 14 days. To validate the drug’s in vivo efficacy, two established posterior fossa EPN PDOX models, ICb-4423EPN and ICb-2002EPN, were utilized. 40 eight weeks old SCID mice per model were implanted with tumor cells. They were divided into 4 treatment groups (10 mice/group) each: 1) control (DPBS, 10uL/kg IP daily x 28 days), 2) radiation/standard therapy (2 Gy focal XRT daily x 5 days), 3) SYC-836 only (15mg/kg IP daily x 28 days), and 4) combination (radiation + SYC-836 per regimen above). Animal survival times were analyzed using log rank analysis. Changes of histone lysine methylation were examined through western hybridization. Results: SYC-836 demonstrated effective cell killing in vitro against both attached and neurosphere cultured cells in both time- and dose-dependent manner. IC50 was ~7.5uM. In vivo experiment was completed in 1 of the 2 EPN PDOX models (ICb-2002EPN) with the second model ongoing. Median survival times for each group is as followed: control 136 days, radiation 148 days, SYC-836 only 136 days, combination 180 days. There were no survival benefit with either XRT only (P=0.205) or SYC-836 only (P=0.186) when compared to the control group; however, when used in combination, the treatment strategy lead to significant improvement in animal survival (P=0.004). SYC-836 was well tolerated in mice. Conclusion: Our data showed that combining SYC-836 with current standard therapy of radiation synergistically prolongs animal survival significantly, although as a single agent SYC-836 was not effective against posterior fossa ependymoma. Our data suggest that SYC-836 may have a role in the clinical setting by either reducing radiation dosages, or be a potential adjuvant agent to other chemotherapy drugs in our treatment approach for ependymoma. Citation Format: Sibo Zhao, Huiyuan Zhang, Lin Qi, Holly Lindsay, Yuchen Du, Mari Kogiso, Frank Braun, Sarah Injac, Laszlo Perlaky, Donald W. Parsons, Murali Chintagumpala, Adekunle Adesina, Yongcheng Song, Xiao-Nan Li. Lysine specific demethylase-1 (LSD-1) Inhibitor SYC-836 in combination with radiation prolongs animal survival in patient-derived posterior fossa ependymoma 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 5058. doi:10.1158/1538-7445.AM2017-5058

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 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