Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

SIMPLE SUMMARY: New treatments are urgently needed for pancreatic ductal adenocarcinoma because it is one of the most aggressive and lethal cancers, detected too late and resistant to conventional chemotherapy. Tumors in most patients feature a similar set of core mutations but so far it has not been possible to design a one-fits-all treatment strategy. Instead, efforts are underway to personalize the therapies. To find the treatments that might work the best for each patient, entirely new experimental platforms based on living miniature tumors, organoids, have been developed. We review here the latest international findings in designing personalized treatments pancreatic cancer patients using organoids as testing beds. Our own work adds important clues about how such testing could, and perhaps should, be conducted. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.