The NSL histone acetyltransferase complex as a therapeutic target for N-MYC-driven neuroblastoma
Neuroblastoma is a form of cancer that typically affects children under the age of five. Infants diagnosed with the most aggressive forms of the disease often die, usually after suffering treatment regimens that can involve combinations of surgery, chemotherapy, radiation, and immunotherapy. Decades of research have established that a protein called "N-MYC" plays a major role in promoting the deadliest forms of neuroblastoma, and made it clear that drugs capable of interfering with N-MYC in neuroblastoma cells would dramatically improve outcomes for children suffering this disease. But N-MYC itself is widely viewed as "undruggable"— it lacks a defined three-dimensional structure that is needed to find small chemicals (drugs) that can dock onto N-MYC and block its activity — meaning that fundamental new breakthroughs will be needed before N-MYC can be tamed to treat neuroblastoma. Our approach to this problem is to not focus on N-MYC, but on its "partners in crime"— the proteins that it uses to cause cancer— and to identify partners within that space that can be drugged. Our efforts with one of these partners is already on a path to the clinic for the treatment of blood cancers. Here we propose a new initiative, with a newly-discovered set of partner proteins, that is focused on neuroblastoma.
Project Goals
This project is based on the innovative hypothesis that one of the key partners N-MYC usesto drive neuroblastoma is a collection of nine proteins not previously implicated in N-MYC function called the "NSL complex." From our preliminary studies, we hypothesize that N-MYC and NSL work together to activate genes that allow neuroblastoma cells to flourish. We further predict that multiple proteins in the NSL complex have three dimensional structures that will support future anti-cancer drug discovery efforts. The overall goal of this project is to lay the foundation for a new way of treating neuroblastoma by drugging members of the NSL complex. Our specific objectives are to test our hypothesis that N-MYC and NSL work together to activate key tumor-sustaining genes in neuroblastoma cells, to probe if NSL is important for the maintenance of neuroblastoma tumors in mice, and to identify the optimal NSL complex members to pursue for drug discovery and the best way to pursue them. If successful, the long-term impact of this research will be the discovery of a new targeted therapy to treat children with aggressive neuroblastoma that is safer, better tolerated, and more effective than today's treatment options.
