Evaluation of anticancer agents using patient-derived tumor organoids characteristically similar to source tissues

Abstract

Patient-derived tumor xenograft models represent a promising preclinical cancer model that better replicates disease, compared with traditional cell culture; however, their use is low-throughput and costly. To overcome this limitation, patient-derived tumor organoids (PDOs) were established from human lung, ovarian and uterine tumor tissues, among others, to accurately and efficiently recapitulate the tissue architecture and function. PDOs were able to be cultured for >6 months, and formed cell clusters with similar morphologies to their source tumors. Comparative histological and comprehensive gene expression analyses proved that the characteristics of PDOs were similar to those of their source tumors, even following long-term expansion in culture. At present, 53 PDOs have been established by the Fukushima Translational Research Project, and were designated as Fukushima PDOs (F-PDOs). In addition, the in vivo tumorigenesis of certain F-PDOs was confirmed using a xenograft model. The present study represents a detailed analysis of three F-PDOs (termed REME9, 11 and 16) established from endometrial cancer tissues. These were used for cell growth inhibition experiments using anticancer agents. A suitable high-throughput assay system, with 96- or 384-well plates, was designed for each F-PDO, and the efficacy of the anticancer agents was subsequently evaluated. REME9 and 11 exhibited distinct responses and increased resistance to the drugs, as compared with conventional cancer cell lines (AN3 CA and RL95-2). REME9 and 11, which were established from tumors that originated in patients who did not respond to paclitaxel and carboplatin (the standard chemotherapy for endometrial cancer), exhibited high resistance (half-maximal inhibitory concentration >10 µM) to the two agents. Therefore, assay systems using F-PDOs may be utilized to evaluate anticancer agents using conditions that better reflect clinical conditions, compared with conventional methods using cancer cell lines, and to discover markers that identify the pharmacological effects of anticancer agents.

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

“…In addition to this, our work highlighted metformin and mTOR inhibitors, such as everolimus, and they have already shown promise in early clinical trials for the treatment of EC [ 190 , 191 , 192 , 193 , 194 , 195 ]. In vitro studies have demonstrated the therapeutic benefit of AURKA inhibitors, cordycepin, genistein, suramin, sodium butyrate and ibrutinib [ 89 , 196 , 197 , 198 , 199 , 200 ]. The MEK inhibitor selumetinib has shown anti-tumour effects in EC cell culture [ 201 ], whilst binimetinib is yet to be studied in EC.…”

Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review

“…There also is evidence for an antiproliferative role of ibrutinib in endometrial cancer. Tamura et al [43] created patient-derived tumor organoids (PDOs) from human tumor tissue (lung, ovarian, endometrial). The morphology, histology, and gene expression of these organoids were similar to their source tumor.…”

Microphysiological Modeling of the Human Endometrium

“…In addition to benign endometrial organoid models, organoids have also been derived from endometrial cancer tissues, and used for drug testing. [65][66][67][68] These endometrial cancer organoids recapitulated genetic and phenotypic characteristics of endometrial tumors, and could be an efficient way of testing therapies. [66][67][68] Organoids have also been derived from the endometrium of patients with other diseases, including endometrial hyperplasia, Lynch syndrome, and endometriosis.…”

“…[65][66][67][68] These endometrial cancer organoids recapitulated genetic and phenotypic characteristics of endometrial tumors, and could be an efficient way of testing therapies. [66][67][68] Organoids have also been derived from the endometrium of patients with other diseases, including endometrial hyperplasia, Lynch syndrome, and endometriosis. 65 Endometrial organoids have provided an alternate physiologic model of the endometrium that can be adapted to biobanking, drug screenings, and investigation of endometrial physiology and pathology.…”