Development of patient‑derived tumor organoids and a drug testing model for renal cell carcinoma

Abstract

The selection of effective therapeutic agents is critical for improving the survival of patients with renal cell carcinoma (RCC). The aim of the present study was to develop an ex vivo drug testing assay using patient-derived tumor organoid (TO) cultures. For this purpose, surgical tumor specimens were obtained from 20 patients with RCC. TOs were developed ex vivo from freshly resected RCC tumors, and their histopathological and molecular characteristics were evaluated using histological staining and whole-exome sequencing (WES). Using a cell viability assay, the therapeutic efficacy of standard of care tyrosine kinase inhibitors in RCC TOs was determined. It was found that TOs recapitulated the histological features of primary RCC tumors. Using WES, a strong concordance was identified at the genetic level between the primary tumors and their corresponding TOs. Using patient-derived TO models, a prototype of an ex vivo drug testing assay was developed, and it was found that RCC TOs exhibited differential responses to sunitinib, pazopanib, cabozantinib, axitinib and sorafenib treatment. On the whole, although the predictive value of the current assay has to be tested and validated in future clinical studies, the findings of the present study demonstrate a novel approach for ex vivo drug testing in patient-derived TO models, which may have potential for use in the personalized treatment of cancer patients.

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies

“…In order to further expand our preclinical pipeline, we aim to use our RCC PDX panel for the development of a 3D-organoid patient-derived platform facilitating ex vivo drug testing assays. Compared to already existing single in vitro approaches ( 58 , 59 ), our combined tool and biostatistics will enable us to increase the predictive power of our patient-derived dataset for the improvement of personalized cancer treatments. In particular, more extensive combination of PDX and in vitro testing of non-responsive xenograft tumors might yield novel therapeutic opportunities for RCC patient tumors with comparable molecular characteristics, at least for specific compound classes.…”

3D organ-on-a-chip: The convergence of microphysiological systems and organoids

“…More importantly, such predictable models can capture specific characteristics of a person’s disease, individual responses to drugs, including side-effects ( Mastrangeli et al, 2019 ). Organoids are now considered as avatars in personalized medicine ( Seidlitz et al, 2018 ; Frappart et al, 2020 ; Jacob et al, 2020 ; Jian et al, 2020 ; Saltsman et al, 2020 ; Shi et al, 2020 ; Witte et al, 2020 ; Bi et al, 2021 ; Kazama et al, 2021 ; Grossman et al, 2022 ) with the potential to contribute to reducing the high level of drug discovery failure. Recent scientific articles related to organoids and drug testing are summarized in Table 2 .…”

Patient-derived organoids potentiate precision medicine in advanced clear cell renal cell carcinoma

“… 25 Kazama et al used PDOs to test the response to several TKIs. 26 However, they both failed to test the response to immunotherapy, since the first generation PDOs failed to preserve immune cells infiltration. However, the significance of immunotherapy is stressed in guidelines and recommended as first-line treatment for patients with metastatic RCC.…”