Bcl2-Family Inhibitors in Neuroblastoma: Mechanism of Action, Therapy Resistance, and Development of Biomarkers
Neuroblastoma is a common tumor that develops in the nerves of the body outside the brain. It is the third most common cancer in childhood after leukemias and brain tumors. It is usually diagnosed in young children, with an average age of 18 months and is the most common cancer diagnosis during the first year of life. Unfortunately, half of the children with neuroblastoma have high-risk features. We can currently cure about half of them despite using intensive therapy that is quite toxic. Neuroblastoma cells are under a great deal of stress from trying to grow abnormally, and even more stress when treatment is started. They need to block all of these stress signals to survive. The mitochondria are the components of a cell that receive all of these stress signals and decide if a cell lives or dies. This happens through special signals communicated by the Bcl2-family of proteins, some of which promote cell death while others block it. A newer category of cancer medications is called Bcl2-family inhibitors which mimic pro-death signals and inhibit survival proteins like Bcl2 and Mcl1. This pushes neuroblastoma towards cell death.
The purpose of this project is to extend our understanding of these Bcl2-family protein interactions and help us target this pathway and kill neuroblastoma cells. Our research findings will help physicians decide how these Bcl2-inhibitors (BCL2i) and Mcl1-inhibitors (MCL1i) should be best used in the clinic, and this same approach can be applied to other tumor types.