Therapeutic downregulation of core circuitry genes in mutant MYOD1 rhabdomyosarcoma

Dr. Berkley Gryder, Ph.D. – Case Western Reserve University School of Medicine, Cleveland, OH

Rhabdomyosarcoma (RMS) is a highly aggressive childhood cancer with poor outcomes, especially in cases with a specific MYOD1 mutation (MYOD1-L122R). This mutation transforms the MYOD1 protein into a powerful cancer driver, leading to a particularly lethal form of RMS. Current therapies have been ineffective, highlighting the urgent need for new approaches. Our research aims to address this need by focusing on two main objectives. First, we will create detailed maps of how genes are regulated in RMS cells with the MYOD1-L122R mutation. By identifying the key genes and pathways controlled by the mutated MYOD1, we hope to uncover the mechanisms that drive cancer progression in this aggressive RMS subtype. Second, we have discovered that drugs targeting the PI3K signaling pathway can significantly reduce MYOD1-L122R activity and slow RMS cell growth in laboratory models. We will investigate how PI3K inhibition impacts the genetic networks controlled by MYOD1-L122R, with the goal of determining whether these inhibitors could serve as an effective treatment option for MYOD1-mutant RMS. This research has the potential to identify new therapeutic targets and explore the effectiveness of PI3K inhibitors in treating MYOD1-mutant RMS, ultimately aiming to improve survival rates for children with this devastating cancer.