Abstract 3848:In vivoevaluation of the LSD1 inhibitor SP-2577 against Ewing sarcoma and rhabdomyosarcoma preclinincal models: A report from the Pediatric Preclinical Testing Consortium (PPTC)

Abstract

Background: Lysine-specific demethylase 1 (LSD1/KDM1A) acts as a transcriptional co-regulator and utilizes flavinadenine dinucleotide (FAD) as a cofactor to remove mono- and di-methyl groups from histone H3 lysine-4 (H3K4) and lysine-9 (H3K9). SP-2577, in contrast to other LSD1 inhibitors in clinical evaluation, is a reversible inhibitor of LSD1. SP-2509 (a tool compound for SP-2577) reversed the EWSR1-FLI1 mediated transcription profile and oncogenic phenotype. To follow-up on these results, the PPTC evaluated SP-2577 against a set of Ewing sarcoma and rhabdomyosarcoma xenografts. Methods: SP-2577 was administered at a dose of 100 mg/kg intraperitoneally (IP) for 28 days and was tested against 7 Ewing sarcoma and 4 alveolar and 1 embryonal rhabdomyosarcoma xenografts. Standard PPTC methods for assessing time to event (EFS T/C = ratio of median time to event for treated versus control animals). Objective response measures similar to clinical measures were applied (Houghton, Pediatr Blood Cancer 2007;49:928-940). Results: SP-2577 was generally well tolerated during the efficacy testing phase. Among 120 animals treated with SP-2577 in efficacy testing, 9 (7.5%) experienced toxic death, and the median maximum weight loss was 1.8% (range 0.0% to 13.7%). As a single agent, SP-2577 induced a statistically significant prolongation in time to event in 3 of 7 Ewing sarcoma models and 4 of 5 rhabdomyosarcoma models. The extent of prolongation of time to event was small for most of the models for which there was a statistically significant prolongation in time to event, with EFS T-C values ranging from 1.9 to 14 days and with EFS T/C values ranging from 1.15 to 2.79. None of the models tested showed objective responses, but rather showed progressive disease as their best response. The minimum relative tumor volumes were significantly smaller compared to control for 4 of 7 Ewing sarcoma models and for 2 of 5 rhabdomyosarcoma models. However, the mean minimum relative tumor volumes were all greater than 1.0, indicating the lack of tumor regression. Pharmacodynamic effects of SP-2577 that were studied included c-Myc, N-Myc, HMOX1, histone H3, and histone H3(K4) dimethyl levels. There were no consistent changes in global histone H3(K4) dimethyl levels, and there was no obvious decrease in either c-Myc or N-Myc, whereas HMOX1 was slightly increased by treatment in two Ewing sarcoma models. Conclusions: SP-2577 was adequately tolerated in the Ewing sarcoma and rhabdomyosarcoma xenografts treatment cohorts that were studied. While a number of the models studied showed statistically significant effects on tumor growth rate, the effect size was generally small and tumor regression was not observed. (Supported by CA199297 and CA199222) Citation Format: Peter J. Houghton, Steve W. Erickson, Beverly Teicher, Malcolm A. Smith, Ruolan Han, Raushan Kurmasheva. In vivo evaluation of the LSD1 inhibitor SP-2577 against Ewing sarcoma and rhabdomyosarcoma preclinincal models: A report from the Pediatric Preclinical Testing Consortium (PPTC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3848.