GENOME ORIGAMI: Refolding Aberrant Chromosome 3D Structure for Treating NUT Carcinoma
NUT carcinoma is an aggressive cancer with a devasting prognosis. It is almost always fatal, with survival measured in months to – at best – two years. This cancer can be diagnosed in children of all ages – from infants to teenagers. NUT carcinoma tumors most often occur in the chest, but can also be found in the head, neck, bones, or soft tissue. NUT carcinoma tumors are caused by a genetic event in which two chromosomes break in half, swap halves, and then fuse back together. This results in a gene fusion that adds a segment of the protein “NUT” to a segment of the protein “BRD4”. This BRD4-NUT fusion protein changes gene regulation. Proper gene folding inside a healthy cell determines if genes are turned on or turned off. We recently discovered that BRD4-NUT performs “genome origami”: it misfolds the DNA inside a cancer cell, resulting in inappropriate gene expression.
Project Goals:
When we discovered that BRD4-NUT misfolds DNA, we also discovered that we could use a drug to refold the DNA back into its proper shape. This is an entirely new concept in how to treat NUT carcinoma and other pediatric cancers in which DNA folding is disrupted, such as Ewing sarcoma and leukemias. Unfortunately, the first class of drugs that block BRD4-NUT from improperly folding chromosomes are too toxic for use in patients. The goal of this project is to identify proteins that collaborate with BRD4-NUT to misfold DNA. By targeting the collaborating proteins, we have a fresh avenue to identify an entirely new class of drugs that are safe and effective for treating patients with NUT carcinoma.
Project Update 2024:
During the first year of this project, we identified that the protein EZH2 cooperates with BRD4-NUT to drive NUT carcinoma tumor growth. When NUT carcinoma mice were treated with a drug combination that targets both BRD4-NUT and EZH2 tumors shrank and all mice were cured. This new drug combination holds great promise for NUT carcinoma patients. We are working on identifying and targeting additional collaborating proteins to provide fresh avenues for discovering entirely new classes and combinations of drugs that are safe and effective for treating patients with NUT carcinoma.
