Glioblastoma multiforme (GBM) is an ultimately lethal disease with a median survival of a little more than one year. Treatment of GBM, by all measures, has shown insufficient and frustratingly slow progress during the last 30 years. At the basic research level, there is a lack of experimental platforms suitable for therapeutic neuro- oncology testing. Rodents have for many years been the mainstay for pre-clinical cancer drug testing and development. However, there are limitations for using rodents for this purpose including differences in the physiology between rodents and humans, and small brain size precluding effective testing of novel surgery, therapies, and imaging technologies. Fitting larger animals include canine and porcine species. The former, although with an innate propensity for developing brain cancer, has considerable ethical and regulatory barriers associated with conducting experimental research whereas the latter is emerging as a very suitable model especially in the form of mini-pigs. These animals have for many years been inbred and developed for transplantation research. However, there are no brain tumor models in such pigs reported in the literature. Herein, we propose to isolate neural progenitors from the Yucatan mini-pig as the precursor cells for malignant glioma development. We will manipulate these cells in vitro with oncogenic CRISPR/Cas9 virus to KO and overexpress critical gene(s) residing on chromosomes associated with gain in glioma to generate immortalized and tumorigenic cells. Subsequently, we will inject these intra-cranially into immune-deficient mice and show tumorigenicity, sustained, and aggressive growth. Ultimately, the pig cells will be injected into Swine Lymphocyte Antigen (SLA)- and blood group-matched pig brains followed by magnetic resonance imaging (MRI) to monitor intra-cranial tumor growth (not part of this R03 proposal). If successful, we expect this pig tumor model to be an excellent, novel testing platform for cancer therapeutics as well as existing and investigational imaging modalities.
At best, standard treatment of glioblastoma multiforme (GBM) prolongs patient survival by a little more than a year, thus there is great need for developing and testing novel therapeutic approaches and tumor models to combat this devastating disease. To facilitate and expand such studies we propose to generate a pig brain tumor model suitable for testing novel imaging modalities and therapeutic agents.
