Abstract 5542: A novel approach for establishing clinically relevant models of chemoresistance

Abstract This study provides a novel methodology for generating in vitro chemoresistance models that maximize clinical relevance, aimed at improving the translatability of downstream experimental insights to clinical contexts. Our approach prioritizes an accurate translation of clinical chemotherapy treatment regimens to in vitro applications. We present our methodology in this study using canine osteosarcoma (OS), but our approach is designed to broadly apply to other cancer types. Chemoresistance poses a significant challenge to improving cancer treatment outcomes, as the underlying mechanisms driving it are not well understood. One approach to studying these mechanisms is generating in vitro chemoresistance models. However, there has yet to be a consensus on the optimal method for developing clinically relevant chemoresistance models. Many existing guidelines either produce levels of chemoresistance that are not clinically achievable or offer incomplete strategies for producing clinically relevant models. To establish a clinically relevant model of chemoresistance, we treated canine OS cell lines with carboplatin under conditions designed to precisely mimic the standard-of-care (SOC) treatment regimen used in clinical practice. To translate this clinical regimen to our in vitro application, we utilized numerous pharmacokinetic parameters derived from serum concentration curves for carboplatin in dogs treated in accordance with the SOC regimen, including area under the curve (AUC), peak serum concentration (Cmax), time to peak serum concentration (Tmax), and time from treatment initiation to when the serum concentration falls below detectable levels. Utilizing these pharmacokinetic parameters, a biphasic treatment protocol was developed to provide a SOC-equivalent treatment regimen for in vitro application. Before commencing model generation, the baseline chemosensitivity of each parental canine OS cell line was determined in triplicate via its respective half-maximal inhibitory concentration (IC50) of carboplatin. These parental cell lines were then split into two identical plates each, with one plate from each cell line treated periodically with our SOC-equivalent regimen, administered every twenty-one days for six cycles, in accordance with the SOC regimen. Untreated cell lines were passaged alongside their treated counterparts as model controls. Twenty-one days after the final treatment, the IC50s of all treated cell lines and their respective controls will be re-assessed in triplicate to quantify the fold change in chemoresistance induced by our SOC-equivalent regimen. We anticipate that treated cell lines will exhibit appreciable increases in chemoresistance, highlighting the potential of our methodology to establish clinically relevant in vitro models of chemoresistance that support future investigations into the underlying mechanisms of chemoresistance. Citation Format: Jared R. Fischbach, Geoffrey A. Wood, Courtney R. Schott. A novel approach for establishing clinically relevant models of chemoresistance [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 5542.

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