Abstract LB162: A multiplex organoid avatar drug testing platform for precision medicine

Abstract

Abstract The promise of precision medicine is to improve patient outcomes by making better therapeutic choices based on cancer causing somatic mutations. This strategy has shown limited success in colorectal cancer, in part because the genetic rules governing resistance and sensitivity are not fully elucidated. Direct drug sensitivity testing of individual patient-derived organoids is an attractive addition to this decision process because it does not require understanding of all drug-somatic mutation interactions. Individual patients avatars can be challenged with a variety of drugs and response used to inform patient care. We have developed a panel of colon cancer organoid avatars and uniquely tagged each one with a lentiviral vector possessing identifying DNA sequence bar codes flanked by common PCR primers. Each bar-code is uniquely identifiable and quantifiable from a mixture of organoids by nanopore sequencing of a common PCR product. Treatment of the mixture of organoid avatars over time under multiple drug conditions and sampling at different time points allowed the real-time monitoring of relative Darwinian fitness of each organoid in the mixture. We demonstrated the utility of this approach at identifying both expected and novel drug responses for individual organoids. Resistance to both nutlin and irinotecan were correctly predicted by TP53 somatic mutations while sensitivity to both lapatinib and ibrutinib were best predicted by mutations in EGFR signaling pathway. Patterns of drug response revealed unexpected common mechanisms. Future work will focus on informing patient care decisions with these results and determining if improvements in patient outcomes are realized. Citation Format: Shrey Patel, Sana Khalili, Victoria Moy, Emma Gray, Sawyer Lyons, Riley Brents, Carolyn Banister, Phillip J. Buckhaults. A multiplex organoid avatar drug testing platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB162.