Modeling and targeting persistence after MYCN inhibition
Neuroblastoma is a devastating childhood cancer that is responsible for ~12% of childhood cancer mortality in addition to significant morbidity among survivors. Better approaches to treating this disease are desperately needed. One of the most important causes of neuroblastoma is when the levels of a gene called MYCN get extremely high in specific cells. This helps change normal cells into cancer cells and then helps the cancer cells grow and spread. Because of this, scientists are trying to make drugs that specifically block MYCN and have made important advances. While these efforts are continuing to progress, we tested some drug-like compounds that block both MYCN and some related proteins. We found that most of the neuroblastoma cells die, but some survive and can grow back. Something similar happens with many therapies we use to treat neuroblastoma and other cancers, in large part because not every cancer cell in a patient’s tumor is the same as every other cancer cell. To cure neuroblastoma, we need better therapies like inhibitors of MYCN, but we also need to understand which cells can survive losing MYCN, how they are different than the other cells, why they survive, and how we can kill them, too.
Project Goals
The goal of this project is to better understand how neuroblastoma cells from a given patient differ from each other, how this impacts whether the cells get killed or not by treatment and how to combine treatments to make sure all the cells get killed. We focus on drug-like compounds that inhibit MYCN, a protein particularly important in neuroblastoma. We have found that some cells can survive MYCN inhibition and grow back, and when they grow back, they are different than they were at the start. One important difference is that they don’t have as much of a molecule called GD2 on their surface. GD2 is important because antibodies that target GD2 are frequently used to treat neuroblastoma. This project will use a number of new technologies to track cells as they are treated with the MYCN inhibitor so that we can understand which cells survive and what is different about them, both before and after treatment. If we can understand how they are different, we can develop therapies to target them. We will also use models of neuroblastoma in mice to test how MYCN inhibitors can best be combined with GD2 antibodies. These studies will provide important information so that we can develop treatments that kill all of the neuroblastoma cells and make sure none are left to cause a relapse.
