Derailing Brain Cancer
At the core of this project is the investigation of a signaling protein, transglutaminase, which Richard A. Cerione, Molecular Medicine/Chemistry and Chemical Biology, believes can contribute to the development and progression of brain cancer—glioblastoma. He and his research group are especially interested in seeing whether this protein helps extend the cellular life of another key oncogenic protein—called the EGF receptor variant type III or EGFRvIII—which is linked to glioblastoma.
The Cerione team and other researchers believe that EGFRvIII plays a critical function in tumor initiator cells (tumor stem cells), and more specifically, in what they refer to as glioma stem cells. It seems that EGFRvIII is especially important in the most aggressive types of glioma stem cells, which are resistant to radiation and some classical types of chemotherapy.
One of the unique features of EGFRvIII is that unlike most conventional signaling proteins, it is not rapidly degraded by cells. For example, it stays around much too long and thus sends persistent signals that enable glioma stem cells to survive and become extremely aggressive. The researchers suspect that transglutaminase plays an important role in ensuring the stability and cellular life of EGFRvIII, as well as in mediating some of its signaling activities.
If that is true, then the researchers want to develop small molecules that selectively target transglutaminase and prevent it from protecting the EGFRvIII. This would ensure that EGFRvIII is degraded and does not remain functional in glioma stem cells for a sufficient period of time and cause them to become aggressive and difficult to kill. NIH Award Number:1R01CA201402-01