Abstract A19: Modeling intrapatient pharmacotranscriptomic heterogeneity with organoids derived from colorectal cancer liver metastases
Authors: Kryeziu Kushtrim , Bruun Jarle , Eide Peter W. , Moosavi Seyed H. , Eilertsen Ina A. , Langerud Jonas , Røsok Bård , Brunsell Tuva H. , Guren Marianne G. , Abildgaard Andreas , Nesbakken Arild , Bjørnbeth Bjørn Atle , Sveen Anita , Lothe Ragnhild A. 
Published: June 2020

Abstract
Patients with metastatic colorectal cancer (CRC) have few targeted treatment options compared with other major malignancies, and both over- and undertreatment with cytostatic drugs remain a challenge. Recent studies show that patient-derived organoids (PDOs) can predict clinical responses to systemic therapies in a personalized manner, but tumor heterogeneity may limit the clinical benefit of anticancer therapies, as well as the accuracy of preclinical predictions. PDO lineage establishment from multiple distinct lesions per patient presents a novel opportunity for preclinical investigation of intrapatient pharmacotranscriptomic heterogeneity. From September 2017 until November 2019, we have established a living biobank of 107 PDOs from 53 patients who underwent resection of CRC liver metastases at Oslo University Hospital, Norway, 31 of whom had multiple (2-5) metastases. All PDOs were screened for sensitivity to 40 anticancer agents, including clinically relevant targeted drugs and conventional chemotherapies. Molecular profiling by gene expression and mutation analyses is ongoing and currently completed for 27 PDOs. Recapitulation of known pharmacogenomic/transcriptomic associations was confirmed in PDOs for EGFR inhibition and RAS/BRAFV600E mutation status, as well as TP53-MDM2 inhibition and TP53 mutation status and TP53 transcriptional activity. Antimetabolites such as gemcitabine and methotrexate, or small-molecule inhibitors in late-stage clinical development targeting Aurora A, PLK1, and HSP90, showed strong differential activities, enabling identification of sensitive subgroups. Strong sensitivity to HSP90 inhibition was associated with low protein expression of Heat Shock Transcription Factor 1, which had a homogenous intrapatient intermetastatic expression pattern. Principal component analyses revealed a clear patient-wise separation of PDOs based on both their pharmacologic and transcriptomic profiles separately, indicating only modest intrapatient heterogeneity among distinct metastatic lesions. Accurate prediction of clinical responses to 5-FU and oxaliplatin was shown in PDOs from one patient treated for recurrent liver metastases. Additionally, PDOs from recurrent liver metastases showed an increased sensitivity to off-label drugs compared to PDOs from the first liver resection, supporting therapy repurposing in later lines of treatment. In summary, patient-derived models of CRC liver metastases reveal modest intrapatient pharmacotranscriptomic heterogeneity—an encouraging result for further efforts to develop personalized drug repurposing strategies for this poor-prognosis patient group.
Citation Format: Kushtrim Kryeziu, Jarle Bruun, Peter W. Eide, Seyed H. Moosavi, Ina A. Eilertsen, Jonas Langerud, Bård Røsok, Tuva H. Brunsell, Marianne G. Guren, Andreas Abildgaard, Arild Nesbakken, Bjørn Atle Bjørnbeth, Anita Sveen, Ragnhild A. Lothe. Modeling intrapatient pharmacotranscriptomic heterogeneity with organoids derived from colorectal cancer liver metastases [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A19.