Evaluating a Novel Methyltransferase Inhibitor for Poor-Prognosis Rhabdomyosarcoma Therapy

Abstract

Rhabdomyosarcoma (RMS) is the most prevalent childhood soft-tissue cancer. While patient outcomes have improved, the survival rate for poor-prognosis RMS, including cases displaying the PAX3-FOXO1 fusion protein in alveolar rhabdomyosarcoma (ARMS), remains low. Novel therapies for these RMS subsets are therefore critical. Here, protein arginine methyltransferase 5 (PRMT5), which was previously identified as being overexpressed in RMS cell lines, was investigated as a novel therapeutic target for poor-prognosis RMS. This study showed that the knockdown of PRMT5 in RMS cell lines using small interfering RNA caused significant decreases in cell proliferation and increased apoptosis. ARMS cell-line growth inhibition and apoptosis was also observed following treatment with the selective inhibitor of PRMT5, GSK591. GSK591 treatment also led to G1 cell cycle arrest and widespread gene expression changes. This study validated the significant downregulation of FGFR4 and IGF2 following GSK591 treatment, suggesting they are potential key players mediating cell growth inhibition. Due to FGFR4 and IGF2 expression being regulated by PAX3-FOXO1, it is hypothesised that inhibiting PRMT5 could result in perturbations of PAX3-FOXO1 activity. Together this project highlights the key role of PRMT5 in RMS tumorigenesis and suggests that PRMT5 inhibitors, such as GSK591, could be promising novel therapeutics for poor-prognosis RMS.

Date of Award	9 May 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Karim T A Malik (Supervisor) & Stefan Roberts (Supervisor)