Abstract IA009: Tumor organoids of multi-metastatic colorectal cancer: From research tools to treatment decision tools
Authors: Sveen Anita , Kryeziu Kushtrim , Klokkerud Solveig M.K. , Berg Kaja C.G. , Totland Max Z. , Bergsland Christian H. , Niederdorfer Barbara , Moosavi Seyed H. , Hofsli Eva , Brændengen Morten , Lassen Kristoffer , Nesbakken Arild , Yaqub Sheraz , Guren Tormod K. , Lothe Ragnhild A. 
Published: December 2022

Abstract
Most patients with colorectal cancer (CRC) do not have an “actionable” target based on molecular tumor profiling. Ex vivo drug sensitivity testing of tumor organoids holds promise as a complementary approach in precision oncology. We have established a pre-clinical pharmacogenomics platform for CRC at Oslo University Hospital. A living biobank of 208 organoids of distinct liver lesions from 100 patients treated by hepatic resection for metastatic CRC was generated in the observational phase of the project. Sensitivity testing of custom drug libraries (n=40-47 drugs) and molecular profiling (targeted DNA sequencing, RNA sequencing, multiplex immunohistochemistry) indicated that the organoids recapitulate well-known pharmacogenomic associations, phenotypic tumor features, and clinical treatment responses (n=35 patients published (ref 1,2)). Evaluation of multiple lesions (n=2-6) per patient suggested diversity among patients in the level of inter-metastatic heterogeneity of drug sensitivities, supporting the need for multi-tumor evaluations in a clinical setting. A collection of CRC cell lines (n=107) was screened for sensitivity to more than 500 drugs and this suggested a molecular basis for response to selected targeted agents, including to PARP inhibition in a small subset of the cell lines (ref 3). Combination screens suggested possibility to overcome acquired resistance to dual BRAF and EGFR blockade in BRAFV600E cells (unpublished data). The living biobank serves as a reference for drug nominations in an ongoing phase II umbrella trial of pharmacogenomics-guided treatment in patients with metastatic CRC (EVIDENT; EU Clinical Trials Register no. 2020-003395-41). Several ad hoc patient cases have been screened as a pilot for the trial, and data of clinical benefit from this functional precision oncology strategy will be presented. References: 1. Bruun J. et al. Patient-derived organoids from multiple colorectal cancer liver metastases reveal moderate intra-patient pharmacotranscriptomic heterogeneity. Clin Cancer Res 2020;26:4107-19. 2. Kryeziu K. et al. Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases. J. Transl Med 2021;19:384. 3. Smeby J. et al. Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity. EBioMed 2020;59:102923.
Citation Format: Anita Sveen, Kushtrim Kryeziu, Solveig M.K. Klokkerud, Kaja C.G. Berg, Max Z. Totland, Christian H. Bergsland, Barbara Niederdorfer, Seyed H. Moosavi, Eva Hofsli, Morten Brændengen, Kristoffer Lassen, Arild Nesbakken, Sheraz Yaqub, Tormod K. Guren, Ragnhild A. Lothe. Tumor organoids of multi-metastatic colorectal cancer: From research tools to treatment decision tools [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA009.