Tumor organoids mirror metastatic GI cancer therapy responses
medwireNews: Tumor organoids derived from metastatic lesions in patients with gastrointestinal (GI) cancers recapitulate patient treatment responses and could have a role in personalized medicine strategies, say researchers.
These patient-derived organoids (PDOs) are miniature, three-dimensional cell cultures that are grown in the laboratory, they explain, adding that thus far the focus has been on organoids derived from the primary tumors, with “sparse” information on PDOs from metastatic lesions.
For the present study – published in Science – the investigators used biopsy specimens from patients with metastatic GI cancers, including colorectal and gastroesophageal cancer, who were enrolled in the phase II PROSPECT-C or FGFR trials, or in the PROSPECT-R or FOrMAT translational research studies.
PDOs were generated from biopsies of liver, pelvic, peritoneal, and nodal metastases, and also from biopsy samples obtained at different timepoints, such as at baseline, time of best response, and disease progression.
Nicola Valeri, from the Institute of Cancer Research in London, UK, and colleagues conducted a raft of histopathologic, molecular, and functional assessments, all of which showed “a high degree of similarity” between the PDOs and the parental tumors.
Furthermore, they observed a correlation between the way the PDOs responded to a certain drug and the clinical response of the patients from whom the organoids were derived. For instance, PDOs generated from baseline biopsy specimens from two patients who demonstrated primary resistance to cetuximab also did not respond to the anti-EGFR antibody.
Similarly, when PDOs from patients treated with the anti-angiogenic multikinase inhibitor regorafenib were transplanted into mice, the animals mirrored the patient responses. Specifically, mice with PDO xenografts from a patient sensitive to the drug showed a significant reduction in their microvasculature, while no significant change was seen in the mice with the resistant PDO xenografts.
And in mice that received PDO xenografts from a baseline biopsy of a patient who initially responded to regorafenib, treatment with the drug led to improved survival versus the vehicle control, but regorafenib did not confer such a benefit in animals xenografted with organoids derived from samples taken after the patient had progressed.
Finally, Valeri et al report that PDOs predicted response to treatment with a sensitivity of 100% and a specificity of 93%, while the positive and negative predictive values were 88% and 100%, respectively.
Taken together, these findings indicate that “PDOs can be exploited for functional genomics to simulate cancer behavior ex vivo and integrate molecular pathology into the decision-making process of early-phase clinical trials,” they conclude.
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