Milan G. Chheda, MD
Assistant Professor, Department of Medicine , Washington University in St. Louis
Druggable Vulnerabilities in IDH1 mutant human neural stem cell models of Glioma
druggable vulnerabilities in idh1 mutant human neural stem cell models of glioma
Glioblastoma (GBM) is the most common and aggressive brain tumor, with an average survival of roughly a year. For years, scientists have focused on finding individual genes that might be driving the tumor, and developing drugs to silence these proteins. In glioblastoma, this has failed, even when we know a specific gene is involved in making a normal cell grow out of control. A good example is the IDH1 mutation, which exists in almost all secondary GBMs. A drug was developed several years ago that shuts mutant IDH1 down, but it does not actually kill tumor cells: it hit its target and did what it was supposed to, but the cells were no longer dependent on the mutation for their survival.
What we propose here is to first design a clinically relevant model for glioblastoma using neural stem cells. We will create two parallel groups of cells: one in which we engineer in the mutant IDH1 gene, and the other without it. After we make the cells, we will characterize the mutant line and compare it to normal, to make sure it truly recapitulates human tumor cells. Then, we will test a large panel of drugs and look for those that specifically kill the mutant, but not normal, cells. This will identify the exploitable vulnerabilities that mutant IDH1 creates. The most exciting part of our work is that we are testing drugs that can be quickly moved into patients.