Disease models

Patient-derived metastatic colorectal, esophageal and biliary cancer organoids could help predict individual patient responses to treatment. The organoids are generated by culturing enzyme-dissociated cells from patient metastatic tumor samples and suspending the dissociated cells in Matrigel. In organoids derived from 21 patients with metastatic colorectal cancer (mCRC), metastatic gastroesophageal cancer or metastatic cholangiocarcinoma, responses to Lonsurf trifluridine/tipiracil, Erbitux cetuximab or paclitaxel measured by cell viability, or to Stivarga regorafenib measured by changes in microvasculature in organoid xenografts transplanted into mice, correctly predicted responses in the corresponding patient with 100% sensitivity and 93% specificity, as determined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Two organoids derived from a gastroesophageal patient -- one derived when the patient was initially paclitaxel-sensitive, the other derived when the disease became paclitaxel-resistant and progressed -- recapitulated the patient’s drug sensitivity and resistance, respectively, and the second organoid exhibited treatment responses similar to those observed in organoids derived from other paclitaxel-refractory patients. Next steps include developing in vitro models of the tumor microenvironment and evaluating how microenvironmental factors affect the organoid responses to treatment.

Taiho Pharmaceutical Co. Ltd. markets Lonsurf, an oral combination of the nucleoside analog trifluridine (FTD) and tipiracil, an inhibitor of the FTD-degrading enzyme thymidine phosphorylase, for mCRC and has the compound in clinical testing for multiple other cancers...