ID #1202 Development of a Porcine Model of Diffuse Midline Glioma

Abstract

Diffuse midline glioma (DMG) is a highly aggressive, inoperable pediatric brain tumor that primarily affects children under 10 years of age and is associated with a median survival of only 9 to 12 months. The diffuse and infiltrative growth pattern of DMG, combined with the incidence in infratemporal and brainstem location, precludes surgical and conventional radiological interventions. Current standard-of-care therapies, such as radiation and chemotherapy, offer only temporary symptomatic relief and limited tumor control. While rodent models of DMG exist, therapeutic strategies effective in these systems have repeatedly failed in clinical translation, likely due to fundamental differences in brain size, anatomy, and physiology between rodents and humans. Therefore, there is an urgent need for a more predictive and clinically relevant animal model of DMG. The pig is proposed as an advanced preclinical model for DMG due to its substantial genetic, anatomical (gyroencephalic brain), and physiological similarities with humans, particularly regarding size, brain structures, and neurodevelopment. The large brain size of pigs putatively permits the emergence of tumors that more closely resemble human DMG in both scale and architecture, enabling the development and assessment of clinically relevant surgical, imaging, and interventional strategies. Furthermore, the longer lifespan of pigs supports longitudinal evaluation of tumor progression and therapeutic response. To address this need, an inducible porcine DMG model has been generated that harbors key genetic alterations commonly observed in human disease, and is designed to recapitulate tumor architecture, growth kinetics, and immunological features. The model incorporates oncogenic histone H3.3 K27M, mutant p53 (R167H), and PDGFRα, stably integrated into the porcine ROSA26 locus with flanking loxP sites to enable Cre-dependent oncogene activation. Transgenic animals were produced by somatic cell nuclear transfer, resulting in a litter of four DMG transgenic pigs. Current studies are focused on validating inducible oncogene expression and evaluating tumor initiation and progression in vivo.