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• W2955558565 abstract "Background: Menin and MLL-containing trithorax complexes play important roles in developmental transcription programs by promoting gene expression through depositing H3K4me3 marks on gene promoters. Menin and MLL1, (lysine methyltransferase 2A, KMT2A) are reported to be overexpressed in Ewing sarcoma. Further, inhibition of the menin-MLL interaction by MI-503 resulted in loss of menin and MLL1, resulting in inhibition of proliferation and tumorigenicity of Ewing sarcoma cells (Svoboda et al., Oncotarget, 2017). VTP-50469 is a small molecule that disrupts menin-MLL1 interactions and is highly active against MLL-rearranged leukemia xenograft models. To extend these results, the PPTC evaluated VTP-50469 in vivo against a set of Ewing sarcoma xenografts. Methods: VTP-50469 was administered twice daily (BID) at a dose of 120 mg/kg or 100 mg/kg orally (PO) for 28 days, a dose and schedule that is highly effective in leukemia MLL-rearranged models. 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: VTP-50469 was generally well tolerated during the efficacy testing phase. Among 70 animals treated with VTP-50469 in efficacy testing, 3 (4.3%) experienced toxic death. As a single agent, VTP-50469 statistically significantly prolonged time to event in 4 of 7 Ewing sarcoma models. In models for which the time to event was significantly prolonged, the extent of prolongation was modest, with EFS T-C values ranging from 3.6 to 7.8 days and with EFS T/C values ranging from 1.24 to 1.74. 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 2 of 7 Ewing sarcoma models. However, the mean minimum relative tumor volumes were all greater than 1.0, indicating the absence of tumor regression. Conclusions: VTP-50469 was adequately tolerated in the Ewing sarcoma xenograft 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. As this dose and schedule of VTP-50469 is highly effective against MLL-rearranged leukemia xenograft models, these results suggest that the menin-MLL1 interaction may play a less critical role in maintenance of Ewing sarcoma. (Supported by CA199297 and CA199222) Citation Format: Peter J. Houghton, Raushan Kurmasheva, Gerard M. McGeehan, Steve W. Erickson, Beverly Teicher, Malcolm Smith. In vivo evaluation of the Menin inhibitor VTP-50469 against Ewing sarcoma preclinical 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 3835." @default.
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• W2955558565 date "2019-07-01" @default.
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• W2955558565 title "Abstract 3835: In vivo evaluation of the Menin inhibitor VTP-50469 against Ewing sarcoma preclinical models: A report from the Pediatric Preclinical Testing Consortium (PPTC)" @default.
• W2955558565 doi "https://doi.org/10.1158/1538-7445.sabcs18-3835" @default.
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