Abstract B040: ResCu: A novel system for predicting and overcoming treatment resistance

Abstract

Abstract Introduction We have developed a novel culturing system, ResCu, that allows for long-term culture of cells without the need for passaging, enabling us to determine treatment resistance that can develop over time. The system creates physiologically relevant conditions to identify resistance pathways most likely to emerge in patients. Using the ResCu Non-small cell lung cancer (NCSLC) model, we identified a synergistic combination of drugs (A+B) and a resistance suppressing combination of drugs (RES-001X: A+B+C) that further extended efficacy. The objective of this study is to evaluate and compare preclinically the in vivo therapeutic efficacy of RES-001X in the treatment of the subcutaneous NCI-H1299 human lung cancer xenograft model in female BALB/c nude mice to the therapeutic efficacy predicted by the ResCu system. Experimental Methods Each mouse was inoculated subcutaneously in the right upper flank region with NCI-H1299 tumor cells (5 × 106) in 0.1 ml of PBS mixed with Matrigel (1:1) for tumor development. Once the mean tumor size reached approximately 80 -120mm3, the mice were randomly allocated to 1 of the following 6 treatment groups: Vehicle (DMSO) Synergistic combination A+B at high dose RES-001X (A+B+C) at high dose RES-001X (A+B+C) at medium dose RES-001X (A+B+C) at low dose Paclitaxel Twice a week, the body weight and tumor volume of the mice was recorded and the study was performed for 90 days with a daily dosing schedule of one of the aforementioned treatments. Results The ResCu system identified a novel resistance inhibiting therapy, RES-001X (A+B+C) that dramatically improved NSCLC tumor response. The synergistic combination A+B resulted in the emergence of treatment resistance and the addition of compound C overcame this resistance. When the ResCu system results were validated against NSCLC PDX models, both the double combination treatment of drug A+B and RES-001X (A+B+C) produced a significant decrease in tumor volume compared to vehicle and paclitaxel. Over the course of the 90-day treatment, the triple combination extended the progression free survival, whereas with the double combination treatment, a resistant cell population emerged and the tumor volume started to increase around the 50 day mark, mimicking the behavior identified in the ResCu system. Conclusion We have developed a novel resistance culturing system, ResCu, and validated it against PDX models with both systems displaying similar treatment resistance behaviors. The ResCu system allows for preclinical testing of cancer therapeutics, and determines the most promising compounds for inhibiting specific resistance pathways and improving treatment efficacy. Citation Format: Christopher Bulow, Manasa Gadde, Lindsay Hill, Nicholas Goldner. ResCu: A novel system for predicting and overcoming treatment resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B040.