A Novel Approach to Target ACVR1 as a Treatment to Pediatric Cancer

Georgia Tech Research Corporation, Atlanta, GA

Brain cancers are the leading cause of cancer-related deaths in childhood. Each year about 300 children in the US are diagnosed with Diffuse Intrinsic Pontine Gliomas (DIPGs), which accounts for 10% of childhood cancer patients. Due to the delicate location of these tumors, surgical resection is not practical, and these patients also do not respond well to current cancer therapies. The survival rate for DIPG patients is less than 20% two years after the initial diagnosis. Therefore, there is a pressing need to develop new, effective therapeutics for DIPGs. Recently, several independent whole-genome sequencing studies on the DIPG tumor tissues have found a new cancer-driver gene known as ACVR1. About 30% of DIPG patients harbor deleterious genetic mutations in their ACVR1 genes, which are believed to contribute to the cause of the disease. Here, the goal is to target ACVR1 in a series of combined computational and experimental studies. By using high-resolution structural data, state-of-the-art virtual screening tools, and experimental validation, two strategies will be adopted to alleviate the deleterious effects of ACVR1 mutations. First, the team will look for novel inhibitors that target ACVR1 mutants found in DIPG patients. Second, the team will look for small-molecule compounds that may restore the regulation of ACVR1. The outcome of the study will suggest possible therapies using repurposed FDA approved drugs for compassionate use or novel small-molecule compounds for clinical trials.