Organoid Based Functional Test To Predict Personalized Treatment In Cholangiocarcinoma

Introduction: It is difficult to find targeted therapies that work across the genetically diverse Cholangiocarcinoma (CCA) patient population; genomic sequencing alone has not resulted in substantial changes in treatment choices for this rare cancer. We reasoned that CCA patients would benefit from a highly personalized diagnostic test, where patient-derived tumor organoids are tested with a library of targeted drugs in a high-throughput functional assay. Methods: Seventeen patients with CCA were enrolled in an IRB-approved ongoing study from 2017 to 2019; biopsies were collected from surgical resection and shipped on ice overnight to a CLIA-certified laboratory (SEngine Precision Medicine) for organoid derivation and high throughput drug testing. Tumor organoids were challenged with up to 120 FDA-approved and investigational drugs to obtain 6-dose, 3-log response curves. Drug responses were benchmarked against an in-house database of pan-cancer patients to concurrently assess both sensitivity and the uniqueness of each patient9s response. Clinical history and genomic information were collected from each patient for retrospective and prospective analysis. Results: 14/19 (74%) samples were successfully derived from 17 patients and screened. Patient age ranged from 36 to 73 (mean=51). The 120-drug library was adapted based on total viable tumor cells per sample, resulting in average of 71 drugs per screen. Top scoring drugs were Ceritinib, MK2206, Belinostat, Taselisib, AZD4547, Everolimus and Poziotinib. In general, the drug sensitivity highlighted the following pathways: AKT, ALK, FGFR, PI3K and EGFR. Drugs were selected per patient and classified as either good or exceptional response and correlated with mutations in known genomic biomarkers in 7 of 12 drug/target pairs. Retrospective analysis demonstrated 100% concordance (n=3) between ex vivo drug resistance and prior treatments. We observed multiple mutation/drug pairs which showed resistance in our functional screen. We achieved a high success rate and clinically relevant turnaround times, from biopsy to final report generation average 17 days (range 9 to 35). Conclusion: This study shows the feasibility of functional testing of organoids derived from CCA patients in a CLIA-certified diagnostic test. While these results correlate well with genomically predicted drug sensitivities, all patients showed additional drug sensitivities beyond those predicted by genomics offering patients additional potential treatment options. This study highlights the importance of functional data in a genetically heterogenous tumor type such as CCA. Each patient represents a mosaic of drug sensitivities, reflecting unique combinations of genetic and epigenetic alterations, and this test can identify the personalized drug combination for them. Citation Format: Astrid Margossian, Franz X. Schaub, Annie Richardson, Michael Churchill, Rachele Rosati, Alexandra Dullea, G Adam Whitney, Hallie Swan, Robert Diaz, Lauren Appleyard, Vijaykrishna Gadi, Ali Zarrinpar, Milind Javle, Christopher Kemp, Shalini Pereira, Carla Grandori. Organoid based functional test to predict personalized treatment in cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 818.