Enhancing AML Treatment: The Synergistic Effect of RP7214 with Gilteritinib and Cytarabine in Preclinical Studies

Promoting the differentiation of immature blasts in acute myeloid leukemia (AML) has emerged as a therapeutic strategy. Dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine synthesis, is a target for inhibiting AML cell proliferation and promoting differentiation. RP7214 is a newly developed DHODH inhibitor that has shown significant inhibition of DHODH activity and proliferation in enzyme and PHA-induced HWB/PBMC assays.

The study aimed to investigate the effects of combining RP7214 with Gilteritinib, an FLT-3 inhibitor, or cytarabine in preclinical AML models. Cell growth inhibition, apoptosis induction, cell cycle analysis, and AKT phosphorylation were assessed in THP-1 and U-937 AML cell lines following treatment with RP7214 and Gilteritinib, either alone or in combination. In vivo anti-tumor efficacy was evaluated in a MV-4-11 mouse xenograft model.

Results demonstrated that RP7214 enhanced the activity of Gilteritinib, leading to significant growth inhibition in AML cell lines. The combination treatment increased the number of apoptotic cells and the proportion of cells in the G2/M phase. Additionally, the combination reduced AKT phosphorylation in THP-1 cells. In the MV-4-11 xenograft model, oral administration of RP7214 showed significant anti-tumor activity as a monotherapy and in combination with cytarabine, with tumor growth inhibitions of 37% and 73%, respectively. The study observed no adverse events or body weight changes.

The findings suggest that RP7214 offers a novel therapeutic approach for AML by enhancing the effectiveness of standard drugs like Gilteritinib and cytarabine. The compound is currently undergoing Phase-1 enabling studies, with human trials anticipated to start in 2020.