Discovery and characterization of novel drugs for treating rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is the most prevalent soft tissue sarcoma of childhood. RMS is a highly undifferentiated cell that arises from a myogenic precursor. There are two major subtypes; embryonal RMS (ERMS) and alveolar RMS (ARMS). ERMS occurs more often, and it is associated with a favorable prognosis, while ARMS is more clinically aggressive, due to a metastatic and recurrence. Despite multimodal treatment, recurrent or metastatic disease has a 5-year survival rates of less than 30%. Therefore, it is important to develop effective drugs for RMS. In this thesis, candidate drugs recommended by an AI algorithm were subjected to drug discovery and characterization for RMS treatment. Conducting a screening test with 18 of the recommended drugs, NDT-IVA was discovered as a hit compound that significantly inhibits RMS cell viability. Invasion assays showed that NDT-IVA reduces the malignant properties of RMS cells. Immunocytochemistry and western blotting identified NDT-IVA that inhibits RMS cells proliferation via the induction of apoptosis. As further studies, RNA sequencing was utilized, and 435 genes were significantly upregulated upon NDT-IVA treatment. According to the RNA-seq results, RT-qPCR for myogenesis markers was undertaken and indicated that NDT-IVA promotes the impaired myogenesis process in RMS cells.