Pancreatic cancer‐derived organoids – a disease modeling tool to predict drug response

Abstract

Background Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date. Methods We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well. Results First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy. Conclusion Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.

Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

“…They subsequently received FOLFIRINOX treatment per clinical performance (figure 6A). ATM inhibition sensitised all PDOs to PAD as revealed by increased cell death ratio (CDR 44 ; figure 6B-C) and increased DNA damage (H2AX p-S139), but a lower proliferation (KI67) ( figure 6D). Interestingly, PDO#5 was the only sample that responded to PAD treatment in the absence of ATM inhibition ( figure 6C and E), although adding the latter still significantly increased cell death rate (figure 6C).…”

Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine

“…Frappart et al created a predictive platform for therapeutic agents based on pancreatic ductal adenocarcinoma organoids. Two analyses were used to assess the effect of drugs, which included measuring the cell death ratio and calculating the area under the curve [ 118 ]. An interesting study by Sharick et al used optical metabolic imaging to assess the metabolic response of breast and pancreatic tumor patient-derived organoids in drug screening [ 119 ].…”

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

“…These results are supported by studies of lung cancer that have indicated a tight interconnection between these two genes [17,34,94]. However, to further determine the regulatory consequences and to investigate the biological and therapeutic relevance of LINC00261 for PDAC growth, invasion, or metastasis, one should consider additional model systems, such as organoids [95][96][97] or mouse models [98,99].…”