MYC as a Driver and Anti-Cancer Target in Malignant Rhabdoid Tumors
Malignant rhabdoid tumor, or MRT, is a rare but devastating childhood cancer. Most children diagnosed with MRT are under the age of two, and most will die from the disease despite intensive surgical, radiological, and chemotherapeutic interventions. A sad reality of MRT is that it is such a rare cancer that drug companies have little interest in developing new ways to treat the disease, meaning that a dismal prognosis is all we can hope to offer the two dozen children who are diagnosed with MRT in the United States every year.
From a genetic perspective, MRT is a simple cancer, typified by mutations in a gene called SMARCB1. The genetic simplicity of MRT, compared to other cancers, should make this disease ultimately very treatable--but only once we understand exactly how mutations in SMARCB1 promote malignancy.
I propose an innovative molecular mechanism through which mutations in SMARCB1 contribute to MRT. I hypothesize that these mutations drive cancer by stimulating the activity of a known pro-tumorigenic gene called MYC. I further propose that, as a result, MRT can be effectively treated by drugs that block the actions of MYC, currently being developed by us and others. The goal of this project is to test this provocative model, and its therapeutic implications, using a combination of biochemical, genetic, and genomic approaches. Completion of this work has the potential to transform our understanding of how MRT forms and how it can be treated.