EPND-05. LYSINE SPECIFIC DEMETHYLASE-1 (LSD-1) INHIBITOR SYC-836 IN COMBINATION WITH RADIATION PROLONGS ANIMAL SURVIVAL IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT (PDOX) MODEL OF POSTERIOR FOSSA EPENDYMOMA

BACKGROUND: Recent molecular subgrouping of ependymoma (EPN) has identified one group, posterior fossa A (PFA), to have one of the worst prognosis and 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, 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 a posterior fossa EPN cell line (ICb-4423EPN) were subjected to SYC-836 at various concentrations (0-25uM). Cell viability and proliferation were measured 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 and divided into 4 treatment groups each: 1) control, 2) radiation, 3) SYC-836 only, and 4) combination (radiation + SYC-836). 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 in both time- and dose-dependent manner. In vivo experiment was completed in 1 of the 2 EPN PDOX models with the second model ongoing. 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. SYC-836 may have a role in the clinical setting by either reducing radiation dosages, or be an adjuvant agent to other chemotherapy drugs in our treatment approach for ependymoma.