Browsing by Author "Lopes, Ana Catarina Cardoso"
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- Patient-derived pancreatic cancer organoids for modeling drug responsePublication . Lopes, Ana Catarina Cardoso; Custódio, Noélia Fernandes; Gomes, Anita QuintalABSTRACT - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, with a five-year survival rate below 10%, for which there is an urgent need for new treatments. The only approved precision drug is a PARP inhibitor (PARPi) in tumors with BRCA mutation, but very few patients benefit from this therapy. Recently, CDK12/CDK13 inhibitors (CDK12/CDK13i) were developed and shown to sensitize cancer cells devoid of BRCA mutations to PARPi. We hypothesized that patients with PDAC could benefit from this combination therapy irrespective of their BRCA mutational status. This project’s main objective was to investigate whether treatment with CDK12/CDK13i sensitizes pancreatic cancer cells to PARPi. As a model system, we used patient-derived organoids. Organoids are three-dimensional primary cultures that maintain a cell architecture resembling the organ from which they were derived. Tumor organoids recapitulate the characteristics of the original tumor and can predict its sensitivity to chemotherapy. In the present study, tissue samples were obtained from patients undergoing surgical resection or fine-needle biopsy. Six PDAC organoid lines were obtained, characterized by hematoxylin and eosin staining and immunofluorescence. Their sensitivity to the drugs carboplatin, PARPi olaparib, CDK12/CDK13i SR-4835, and the combination of olaparib with SR-4835 were tested. The PDAC organoids tested are not sensitive to carboplatin but are sensitive to SR- 4835. The response to olaparib is patient-dependent, with only one PDAC organoid line being sensitive. The combination of olaparib with SR-4835 is synergistic in all the cases, except for the one sensitive to olaparib.