Investigating Revumenib for Targeted Epigenetic Therapy in Pulmonary Arterial Hypertension

About This Grant

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a rare and progressive cardiopulmonary disorder characterized by the remodeling of pulmonary vascular cells, which leads to narrowing and the obstruction of pulmonary arteries. This results in increased pulmonary vascular resistance and pressure, ultimately causing right ventricular failure. Despite current therapies targeting key pathogenic pathways, the morbidity and mortality associated with PAH remain unacceptably high, highlighting the urgent need for new treatments. A hallmark pathological feature of PAH is the phenotypic shift of pulmonary artery smooth muscle cells (PASMCs) to a “cancer-like” state, which is characterized by hyperproliferation and resistance to apoptosis. Previous studies have suggested that abnormal histone methylation contributes to this pathological phenotypic switching, promoting uncontrolled vascular remodeling during the early stages of PAH. However, the precise molecular mechanisms involved are still poorly understood. Menin (Men1), a scaffold protein that interacts with the histone methyltransferase Mixed Lineage Leukemia 1 (MLL1 or KMT2A), plays a crucial role in regulating gene expression through epigenetic mechanisms, including the trimethylation of H3K4me3 histone marks, which influences oncogenic pathways and cell cycle control. While its role in cancer is well established, the involvement of the Men1/MLL1 complex in the pathogenesis of PAH has yet to be elucidated. In this proposal, we aim to elucidate the role of this complex by investigating how Men1 contributes to the phenotypic reprogramming of PASMC and vascular remodeling in PAH. Importantly, we will evaluate the therapeutic potential of Revumenib, a potent and selective Men1/MLL1 complex interaction inhibitor, in both in vitro and in vivo preclinical models of PAH. Our preliminary results show an upregulation of Men1 and MLL1 levels in both human PAH lung tissues and a rat model of PAH. Treatment with Revumenib led to a reduction in Men/MLL1 expression and interaction, accompanied by a decrease in H3K4me3 histone marks and reduction of PASMC hyperproliferation and migration. Based on these findings, we hypothesize that Men1 exacerbates vascular remodeling in PAH via MLL1-mediated H3K4me3 marks and associated transcriptional gene programs, thereby promoting the reprogramming of PASMCs. SA1 will evaluate the in vitro efficacy of Revumenib in PAH-PASMCs by examining its effects on cell proliferation, apoptosis, and gene expression signatures associated with Men1/MLL1 activity. SA2 will assess the in vivo therapeutic potential of Revumenib in healthy and in rat models of PAH. Biochemical and cellular assays will be used to evaluate drug distribution, Men1/MLL1 complex disruption, and downstream epigenetic modifications and signaling in the lungs. Given Revumenib’s promising safety profile in previous human and animal studies in acute myeloid leukemia, we anticipate minimal adverse effects in the context of PAH. The successful completion of this project will enhance our understanding of epigenetic regulation in PAH and may establish Revumenib as a foundation for the development of a novel, mechanism-based treatment strategy for this rare, deadly disease.