Interrogation of Neuroblastoma Dependencies and RNAs on the Core-Regulatory Circuitry for Therapeutic Inhibition
Neuroblastoma (NB) is one of the most common solid tumors of childhood. Despite multimodality therapy, nearly half of patients with high-risk neuroblastoma will die of this disease. High-risk neuroblastoma typically has many DNA copies of the MYCN gene. I recently identified a group of six proteins which work together to form a network to drive neuroblastoma. Disrupting any one of these proteins causes all to be lost and the tumor cells to die. Unfortunately, there is no known way to target MYCN or these other proteins right now.
Here, I will perform experiments to identify new roles for uncharacterized RNAs that are likely to be involved in regulation of the network. Further, I will use chemical inhibitors to disrupt proteins that NB cells require for survival, several of which likely regulate these key factors. These new proteins will also be inhibited in animal models of human neuroblastoma, alone and in combination with drugs similar to those entering clinical trials for NB.
These studies aim to identify new levels of gene regulation and methods to inhibit the genes that establish the cell identity of NB, with minimal side effects.