Glioblastoma (GBM) is an aggressive primary brain tumor with no effective cure. Standard of care treatment offers dismal prognoses for patients with a median survival time of only 15.6 months, and no new drugs have been approved in 15 years. Contributing factors include tumor heterogeneity, high mutation rates, infiltrative growth, a complex tumor-immune microenvironment, and the blood-brain barrier, all of which are obstacles clinicians and researchers must overcome to improve patient outcomes. Research to identify novel therapeutic strategies are ongoing, but treatments that show promise in preclinical studies often do not pass Phase 2 and 3 clinical trials. These costly failures are attributable to a lack of predictive preclinical models that translate to human application, low patient availability for numerous and robust clinical trials, and an “all-comer” approach to clinical trial design where patients are enrolled based on disease presence and not molecular features of the tumor. To advance treatments for GBM, Recombinetics has pioneered somatic gene-editing technologies to the same genetic changes seen in patient tumors in GBM-initiating cells in an immune-competent swine model. These models rapidly and reproducibly develop GBM tumors that resemble human GBMs genetically, clinically and histologically. In addition to the physiological, immunological, and metabolic parallels between swine and humans, the molecular data collected from our swine mesenchymal and classical subtypes of GBM validate accurate disease modeling and we are pursuing additional GBM subtypes. Using RNA-sequencing, we are characterizing molecular profiles of these tumors, as well as identifying and validating drug targets. Studies are ongoing to characterize the tumor immune microenvironment of our models for improved immune-oncology therapeutic development. These large animal models of GBM will usher in a new era of pre-clinical testing that predicts the efficacy of a variety of therapeutic approaches, using precision medicine to bring novel, safe, and effective therapies to patients.
Glioblastoma (GBM) is the most common and malignant primary brain tumor. Novel therapeutic development for GBM is desperately needed, as the standard of care universally fails to cure patients and the 5-year survival rate remains extremely low. GBM therapeutic development is hampered by the lack of relevant preclinical models for preclinical studies. To mitigate this problem, we have developed a genetic 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 in vivo by direct injection of gene delivery reagents to the lateral ventricle, altering major signaling pathways frequently changed in human GBM. 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. We have altered six major human GBM-associated signaling pathways and modeled molecular GBM subclasses. We have also engineered a secreted tumor reporter that can be used to monitor tumor size through a simple blood test. This somatic cell gene-modification platform we have developed in the minipig allows us to reproduce the genetic heterogeneity seen in GBM and understand the impact of the tumor microenvironment, immune system, and response to therapy. This minipig model of GBM Is being used to test the standard of care against novel therapies in preclinical studies, and biopsy, surgical, imaging, and radiation therapy techniques are being optimized in this mode to improve clinical trial success rates and patient outcomes. Funding for this study is provided by the National Institutes of Health though SBIR grant # 1R43CA235837-01A1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.