Abstract 2834: Establishment of orthotopic high grade glioma xenograft model using zebrafish embryos

Abstract

Abstract High grade glioma (HGG) is the most common malignant brain tumor in adults. These tumors represent a lethal group of brain tumors characterized by a remarkable level of genetic, epigenetic, and environmental heterogeneity, which can significantly affect therapy response and patient outcomes. Patient-derived xenograft (PDX) models of glioma are a central tool for neuro-oncology research and drug development, enabling the detection of patient-specific differences in growth and drug response. Mouse xenografts of HGG are well-established, but the time required to generate these models is not practical for integration into clinical paradigms. Patient derived organoids cannot mimic the physiologic aspects of an in vivo system, such as the blood-brain barrier or metabolism of drugs, which can affect how tumor cells respond to treatment. In this context, zebrafish are emerging as a time-efficient and cost-effective in vivo model. We investigated a rapid zebrafish-based PDX model that can recapitulate key aspects of different gliomas and enable treatment response evaluation within 8 days. We engrafted one GBM cell line (U-87), two patient-derived glioblastoma (GBM) cells, and one patient-derived IDH mutant grade 4 astrocytoma into the midbrain region of 2-day-old zebrafish embryos. Survival of transplanted larvae were monitored over 8 days post-transplantation and the engraftment was analyzed. Therapy response was evaluated through tumor size. One day post-transplantation, animals received 10 and 25 Gy radiation with or without 50 and 100 µM of temozolomide, a common GBM therapeutic, and tumor size was measured after 3 days by imaging. Results showed that GBM and astrocytoma cells had 100% and 80% of engraftment, respectively. GBM cell induced a median survival of 7 days in transplanted animals while 87 % of astrocytoma-injected animals were alive 8 days post transplantation. GBMs also varied in their drug and radiation response. Although both samples were classified as high-grade GBM and MGMT unmethylated, PDX derived from a younger patient with no alterations in PTEN and MDM2 genes responded better to temozolomide and radiation. Tumor responsiveness to therapy is often a combination of genetic and non-genetic factors that are difficult to clinicians to predict. By combining tumor-specific models and drug testing, a patient’s treatment plan could be tailored based on the sensitivity of each sub-clone to targeted therapeutics. In conclusion, we showed that the zebrafish-based PDX model provides a novel, high throughput avenue to assess the impact of tumor heterogeneity on drug response. Citation Format: Evelyn Winter da Silva, Annick De Loose, Yelena Chernyavskaya, Analiz Rodriguez, Jessica Blackburn. Establishment of orthotopic high grade glioma xenograft model using zebrafish embryos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2834.