Inhibition of translation initiation as a novel therapeutic strategy against MYCN-amplified neuroblastoma
The goal of this project is to test a novel strategy for disrupting the effects of MYCN amplification, which is seen in over 50% of high risk neuroblastoma patients. Although the association of MYCN amplification with a poor outcome is well established, attempts to directly target MYCN have been challenging. Therefore, we propose to tackle one of the consequences of amplified MYCN that enables abnormal cell growth, that of increased protein expression (translation). Proteins are the “doers” in the cell and originate from RNA. MYCN amplified cells have increased levels of protein production. We plan to disrupt such protein synthesis in MYCN-amplified neuroblastoma using novel small molecule inhibitors of one of the first critical steps in converting RNA into protein - translation initiation. This new class of compounds specifically target eIF4A, a molecule that is critical for translation initiation. We have identified a candidate compound that kills MYCN-amplified neuroblastoma cells while sparing normal cells. In this application, we plan to ensure that such a strategy is clinically feasible by testing it in animal models of human neuroblastoma, and to study the mechanism by which this class of inhibitors selectively targets neuroblastoma cells with MYCN amplification. Our studies will provide preclinical validation of this novel group of compounds that can then be taken forward into clinical development.
Project Goals:
The goal of this project is to test a novel strategy for disrupting the effects of MYCN amplification, which is seen in over 50% of high risk neuroblastoma patients. Although the association of MYCN amplification with a poor outcome is well established, attempts to directly target MYCN have been challenging. Therefore, we propose to tackle one of the consequences of amplified MYCN that enables abnormal cell growth, that of increased protein expression (translation). Proteins are the “doers” in the cell and originate from RNA. MYCN amplified cells have increased levels of protein production. We plan to disrupt such protein synthesis in MYCN-amplified neuroblastoma using novel small molecule inhibitors of one of the first critical steps in converting RNA into protein - translation initiation. This new class of compounds specifically target eIF4A, a molecule that is critical for translation initiation. We have identified a candidate compound that kills MYCN-amplified neuroblastoma cells while sparing normal cells. In this application, we plan to ensure that such a strategy is clinically feasible by testing it in animal models of human neuroblastoma, and to study the mechanism by which this class of inhibitors selectively targets neuroblastoma cells with MYCN amplification. Our studies will provide preclinical validation of this novel group of compounds that can then be taken forward into clinical development.
Project Update 2024:
The goal of this project is to test a new strategy for disrupting the effects of MYCN amplification, using a series of compounds that inhibit the first step in protein synthesis, translation initiation. Over the first year of this award we have made several strides in accomplishing the goals of the project. We tested a number of inhibitor compounds, and observed that they confer selective effects on MYCN-amplified cells. We have performed experiments to determine the mechanism by which these classes of inhibitors inhibit MYCN-driven protein synthesis. In the second year, we plan to test our optimized candidate in animal models of neuroblastoma and to further home in on the types of genes whose functions are inhibited through this strategy.
