Abstract 5106: Pharmacological targeting of LSD1 prolongs animal survival times in patient derived orthotopic xenograft models of posterior fossa ependymoma in combination with fractionated radiation

Abstract Background: Posterior Fossa Group A Ependymoma (PFA EPN) constitute one of the most aggressive and highly recurrent molecular subtypes of childhood Ependymomas. We recently performed a comprehensive genome-wide DNA methylation analysis in recurrent pediatric EPN tumors from patients that were followed up for over 13 years. Integrative analysis between tumor DNA methylation and histone modification identified LSD1 as a druggable driver of PFA EPN recurrence. In this study, we examined the therapeutic efficacy of our newly developed LSD1 inhibitor SYC-836 in PDOX models of recurrent PFA EPN. Methodology: To determine the in vitro anti-tumor activities of SYC-836, paired PFA EPN xenograft cell cultures (monolayer and 3D neurospheres) were treated with SYC-836 at 8 concentrations (0.02-25 µM) and examined for changes of cell proliferation every 3-4 days through day 14. To validate the drug’s in vivo efficacy, two established posterior fossa EPN PDOX models, ICb-4423EPN and ICb-2002EPN, were utilized. Forty 8-week old SCID mice of both genders received intra-cerebellar tumor cell implantation and were divided into 4 treatment groups (n=10 per group): 1) control, 2) radiation (2 Gy/day x 5 days), 3) SYC-836 (15 mg/kg, daily intra-peritoneal injection for 28 days), and 4) combination (radiation + SYC-836). Animal survival times were analyzed using log-rank analysis. Changes in LSD1 protein expression and histone lysine methylation were examined through western hybridization. Results: SYC-836 strongly suppressed PFA EPN cell growth in vitro, in both, a time- and dose-dependent manner. While there was no survival benefit with either SYC-836 only (P=0.186) or XRT only (P=0.205); combining SYC-836 with XRT significantly (P=0.04) prolonged the median survival time of ICb-4423EPN, from 46 days in the untreated group to 59 days; and in ICb-2002EPN, even more prominent, from 136 days to 180 days (P=0.007). SYC-836 was well tolerated in mice with no loss of body weight or other toxicities. Changes in LSD1 protein expression and H3K4me2 were detected through western hybridization during and after SYC-836 treatment. Conclusion: Our data support LSD1 as a druggable driver of PFA recurrence and highlights strong anti-tumor activities of SYC-836 in combination with radiation, a standard therapy of pediatric EPN. 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. Citation Format: Milagros M. Suarez Palacios, Sibo Zhao, Huiyuan Zhang, Lin Qi, Holly Lindsay, Mari Kogiso, Frank Braun, Adekunle M. Adesina, Yuchen Du, Yongcheng Song, Xiao-Nan Li. Pharmacological targeting of LSD1 prolongs animal survival times in patient derived orthotopic xenograft models of posterior fossa ependymoma in combination with fractionated radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5106.