Functional Dissection of EZH2 in Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine glioma, or DIPG, is a highly aggressive fatal brain cancer that mostly strikes young children. There are approximately 200-300 children diagnosed with DIPG in the United States each year. In DIPG, the tumor encompasses nearly the entire pons, a part of the brainstem required for survival as it regulates our blood pressure, heart rate, and breathing. DIPG tumor cells are infiltrative, invading around normal brainstem cells, which is why brain surgeons cannot remove the tumor. The median survival rate is less than one year after diagnosis. To date, there are no medications that have proven to be beneficial for treatment of these cancers. In fact, the standard of care today for children diagnosed with DIPG in the United States is the same as it was in the 1970s. This tumor is understudied partly due to the limited availability of DIPG tissue and cell-lines, which is why the development of genetic mouse models of DIPG is important. More recently, an abnormal protein called a histone was discovered in the majority of DIPGs. The normal function of this protein is to package our genetic code in the cell nucleus and to act as a switch to turn genes on and off. My lab has developed a genetic mouse model of DIPG that incorporates this abnormal protein. Preliminary studies suggest that the abnormal protein inappropriately turns genes ON and OFF (genes that are supposed to be ON get turned OFF and genes that are supposed to be OFF get turned ON). In this proposal, I am going to study which genes that are inappropriately turned ON or OFF by the abnormal protein contribute to DIPG formation. Novel insights from this work will open up new therapeutic strategies against this tumor.