Capitalizing on functional genomics with targeted protein degradation in neuroblastoma
Children with solid tumors have poor overall survival. Further, the treatments used for these diseases are very toxic. One particularly difficult to treat pediatric solid tumor is called neuroblastoma (NB). Children with neuroblastoma are treated with very toxic therapies, and even so, many of them will not be cured. In addition, while large-scale studies have identified the specific proteins that NB cells depend on for growth, these proteins are especially hard to target with traditional drugs. This limits our ability to treat NB effectively. However, a new method called targeted protein degradation (TPD), may be able to effectively target these proteins. We tested over 4,000 different TPD compounds in NB cells. Using this test, I found 1 compound that was very effective at killing NB with MYCN-amplification. Here, I will examine how this MG works, discover its cellular target and determine if this new compound can be used in animal models of NB. Importantly, many different types of cancer, including other high risk pediatric tumors like rhabdomyosarcoma, osteosarcoma, and rhabdoid tumors, also rely on difficult to target proteins, so this work may act as a roadmap for future studies in many different diseases, while also investigating neuroblastoma.
Project Goal:
Children with neuroblastoma have poor overall survival. Further, the treatments used have enormoustoxicities. Despite significant inquiry, children with relapsed neuroblastoma (NB) have limited treatment options, because relapsed tumors become resistant to even our best therapies. NB cells depend on specific proteins to grow, but these proteins are hard to target with traditional drugs. The overall goals of this project are to evaluate a new preclinical treatment strategy that holds promise for being more effective at killing NB cells and less toxic than our current treatment regimens. In doing so, I will identify how a new class of drugs works in both NB cells and in animal studies that closely resemble that of the true patient environment. This will also be of great importance in the larger pediatric cancer community where other high risk pediatric tumors like rhabdomyosarcoma, osteosarcoma, and rhabdoid tumors, as well as many others, also rely on a cohort of such difficult to target proteins.
