Abstract 6282: EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML
Conferences
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
AbstractMETTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p<0.01, relative to vehicle control) inhibited cancer progression as measured by in-life imaging in addition to flow cytometry of hCD45+ cells in bone marrow, blood and spleen; M3i had minimal effects on hematopoiesis in this model with no significant changes in RBCs, WBCs and neutrophils, but an increase in platelets (measured by IDEXX). In an orthotopic, patient-derived xenograft model of AML (LEXF 41283, intratibial implantation, female NSG mice), M3i (30 mg/kg, i.p., QDx91 days) significantly prolonged survival (p<0.01, relative to vehicle control) with a commensurate absence of hCD45+ cells following compound treatment. These results confirm that the pharmacological inhibition of METTL3 is a viable strategy for the treatment of AML and support the additional exploration of the role of METTL3 inhibitors in alternate blood cancers as well as solid tumors.Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6282.
