The focus of the MIT/Mayo PS-OC is to understand the physical and biological features of primary and metastatic brain tumors that result in heterogeneous drug delivery and how sub-therapeutic delivery may impact treatment failure and resistance emergence. The studies in this PSOC will focus on evaluating a spectrum of EGFR- and RAF-targeted therapies in patient-derived xenograft (PDX) orthotopic models of glioblastoma (GBM) and melanoma brain metastases. The Animal and Pharmacology Core will provide critical infrastructure, expertise and experience to support these studies. The Core will be led by Dr. Jann Sarkaria, who has extensive expertise in animal tumor models and by his long-time collaborator, Dr. William Elmquist, who is an expert in pharmacokinetic modeling of drug delivery into the brain.
Glioblastoma (GBM) patient-derived xenograft (PDX) models have been developed to overcome the limitations of more traditional glioma models and have become one of the gold-standards for both basic and translational studies in GBM. The Sarkaria laboratory has developed a panel of 79 GBM xenografts that were established by implanting patient tumor specimens directly into the flank of nude mice. Maintenance of these xenograft lines by serial transplantation in mice preserves key genetic features of the corresponding patient tumor, such as EGFR amplification, and whole exome sequencing and RNAseq analysis demonstrates that these models are broadly representative of common molecular variants observed within GBM. We used a similar strategy to xenograft freshly resected brain tumor metastases to develop highly translational relevant models for brain metastases. To date, we have developed 38 brain metastasis PDX models, including 11 from melanoma metastases. These melanoma PDX models demonstrate robust intracranial growth when directly implanted into the brain, significant brain tropism following intracardiac injection, and similar to the glioma PDX models, we are completing our RNAseq analysis of these models. Overall, the extensive phenotypic and molecular characterization of these models greatly enhances our ability to select appropriate tumor models to test the EGFR and RAF-targeted therapies in the planned MIT/Mayo PS-OC projects.
The Animal and Pharmacology Core will provide essential services to the MIT/Mayo PS-OC in support of both Project 1 and Project 2. The Core will manage all aspects of the experiments that involve live animals and, in collaboration with the Administrative Core, manage distribution of biospecimens and imaging data to the appropriate investigators.