We have developed a suite of genetically-engineered mouse models of human gliomas and ependymomas that we have used to inform treatment options for clinical agents. High-grade gliomas are fatal in nearly all cases because of the inability to fully resect them, and the resistance of the remaining tumors cells to available therapy. There are two main molecular subtypes of glioma, those less aggressive tumors with IDH1 mutation and a methylator phenotype designated CIMP, and the more aggressive non-CIMP gliomas that are frequently grade 4 GBMs. The treatment of these tumors is surgery followed by radiation and chemotherapy for high-grade gliomas, with almost uniform recurrence and a median survival of less than 2 years. We clearly need improved strategies for treating these brain tumors, partly by enhancing radiation therapy and partly by getting the immune system to work better at attacking these tumor cells. In this grant we will develop these methods in mice via nanoparticles and biopolymers. This grant application is an opportunity to gather a team of leading experts in these fields to use GEMM models of these tumor types to advance these areas. In each case we will be developing technology in these models that can be translated to human trials within a few years.
We have developed a suite of genetically-engineered mouse models that are demonstrably representative of IDH1 wild type and mutant human gliomas. These models have been used to inform treatment options for clinical agents, and this now enables us to propose these models are suitable test-beds for testing potential major improvements to how these diseases are treated. In this grant we will use these models to help understand and develop immune therapy strategies for glioma.
