Organoid Level Assessments of Human Primary and Metastatic Colorectal Cancer-Derived Organoids Predict Response to Chemotherapy and Chemoradiation

Background: Therapies for metastatic colorectal cancer (CRC) are largely chosen without considering inter-patient heterogeneity, leading to unnecessary side effects without clinical benefit for some patients. Patient-derived cancer organoids (PDCOs) faithfully recapitulate the morphology and molecular profiles of the primary tumors from which they are derived, making them attractive preclinical models for predicting response to standard therapies, and thus, for use in drug development assays. Methods: Here, we investigate the hidden subclonal driver mutations in CRC PDCOs and the importance of individual PDCO-level heterogeneity when addressing PDCO treatment responses using changes in diameter and optical redox imaging. PDCO response is then compared to clinical response across a cohort of subjects with CRC receiving chemotherapy and/or chemoradiation. Results: Change in diameter and optical redox imaging are more sensitive to detecting therapeutic response than endpoint and well-level measurements. These measurements accurately reflect clinical responses to chemotherapy and chemoradiation. Conclusions: Overall, these studies demonstrate the importance of PDCO-level methods of PDCO assessment and further establish PDCOs as powerful tools for drug response assessment and developmental therapeutic studies.