Abstract 4756: Novel anaplastic thyroid carcinoma patient-derived xenograft models and cell line

Abstract Introduction: Anaplastic Thyroid Carcinoma (ATC) is the deadliest thyroid malignancy with a historic median overall survival of 5 months. Its highly aggressive nature limits our ability to test novel targeted therapies in patients. Patient-Derived Xenograft (PDX) models and cell lines are considered reliable preclinical models to test novel therapies as well as drug combinations. Aim: Our group has previously reported ATC PDX model development, although certain key genetic mutations frequently found in the clinical setting are lacking. Our goal is to report our experience developing and characterizing three novel PDX models and one paired cell-line that have pathologically and clinically relevant mutations that may be used for drug development and testing. Methods: Fresh tumor from ATC patients was harvested at the time of surgery and cut into 4x4x4 mm pieces and implanted subcutaneously in 5-8-week-old nu/nu female nude mice. Tumor was measured with a calibrated tool every 2 weeks. Mice were euthanized when the tumor reached 1000 mm3. Tumor was then harvested and transferred into a new generation of mice. Tumor samples were used to confirm genotyping by Short Tandem Repeats DNA fingerprinting as well as interspecies contamination testing to compare the fractional abundance of human versus mouse DNA. H&E staining, immunohistochemistry (IHC), and PCR were done to confirm microscopic, IHC, and genetic similarity to the original patient tumor, respectively. Successful PDX establishment was defined by successful engraftment (F0), tumor passaging through 4 consecutive generations (F1-F4), and successful tumor growth from a cryopreserved sample. A cell line was developed by collagen and extracellular DNA degradation, RBC removal, followed by incubation in RPMI medium. A total of 20 passages and at least 6 months in culture were considered adequate to deem a cell line as established. Results/Discussion: Three novel ATC PDX models were successfully established. MDA-ATC8 is a BRAF wild type (WT) and TP53, NRAS_Q61K, TERT, ASXL2_G853S, ERBB4_D243N, INHBA_I410T mutant ATC model, from a patient previously treated with dabrafenib, trametinib and pembrolizumab (DTP). This is the only established model with a paired cell line (MDA-T317). MDA-ATC9 is a BRAF, RAS, and TERT WT tumor with TP53, FGFR2, LRP1B, and MEN1 mutations. Tumor was harvested from a previously untreated patient. MDA-ATC11 is a BRAFV600E, P53, TERT, ABL1, KMT2C, LRP1B, RICTOR mutant derived from a patient previously treated with DTP. Conclusion: We report the development and establishment of three new ATC PDX models with one paired cell line. These models show excellent compatibility with their human tissue counterparts, making them highly reliable as preclinical models. Furthermore, with novel drugs being developed for RAS_Q61 mutation, MDA-ATC8 may play a major role in testing potential candidates for this untreatable patient population in the near future. Citation Format: Ahmad Abubaker, Ying Henderson, Marie-Claude Hofmann, Naifa Busaidy, Maria E. Cabanillas, Michelle Williams, Anastasios Maniakas, Stephen Y. Lai. Novel anaplastic thyroid carcinoma patient-derived xenograft models and cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4756.