TMOD-20. A SWINE MODEL OF GLIOBLASTOMA INDUCED BY SOMATIC GENE MODIFICATION

Abstract Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is needed since the standard of care universally fails to cure patients and the five-year survival rate remains below 10%. GBM therapeutic development is hampered by the lack of relevant large animal models for preclinical studies. To mitigate this problem, we are developing a model of GBM in outbred, immune-proficient swine which have comparable brain size and anatomy to humans. We developed methods for introducing genome engineering tools to minipig brain cells in vivo by direct injection of gene delivery reagents to the lateral ventricle. Using this technique, we have delivered a combination of expression vectors for oncogenes and targeted nucleases to disrupt tumor suppressor genes commonly altered in human GBM to alter six major human GBM-associated signaling pathways in a cohort of minipigs (Ras, Pi3k, p53, Rb/E2F, Pdgf, and the alternative lengthening of telomeres (ALT) pathways). These minipigs are being monitored for tumorigenesis using a secreted reporter, detectable through a simple luminescence-based blood test. Resulting tumors will be examined molecularly to detect the pathway-associated alterations in tumor tissue and determine the resemblance to human GBM. We hypothesize that this somatic cell gene-modification platform we have developed in the minipig will facilitate the efficient production of brain tumors that histologically and genetically resemble human GBM. It will allow the production of tumors that are genetically heterogeneous, of specified molecular subclasses, containing therapeutic targets of interest, and in the context of genetic backgrounds of interest. This minipig model of GBM will be applied towards preclinical therapeutic studies, imaging studies using human clinical grade equipment, and surgical technique development, to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health through SBIR grant # 1R43CA235837-01A1.