Screening of an individualized treatment strategy for an advanced gallbladder cancer using patient-derived tumor xenograft and organoid models

Abstract

Gallbladder cancer is a highly aggressive malignancy with poor sensitivity to postoperative radiotherapy or chemotherapy; therefore, the development of individualized treatment strategies is paramount to improve patient outcomes. Both patient-derived tumor xenograft (PDX) and patient-derived tumor organoid (PDO) models derived from surgical specimens can better preserve the biological characteristics and heterogeneity of individual original tumors, display a unique advantage for individualized therapy and predicting clinical outcomes. In this study, PDX and PDO models of advanced gallbladder cancer were established, and the consistency of biological characteristics between them and primary patient samples was confirmed using pathological analysis and RNA-sequencing. Additionally, we tested the efficacy of chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitors using these two models. The results demonstrated that gemcitabine combined with cisplatin induced significant therapeutic effects. Furthermore, treatment with immune checkpoint inhibitors elicited promising responses in both the humanized mice and PDO immune models. Based on these results, gemcitabine combined with cisplatin was used for basic treatment, and immune checkpoint inhibitors were applied as a complementary intervention for gallbladder cancer. The patient responded well to treatment and exhibited a clearance of tumor foci. Our findings indicate that the combined use of PDO and PDX models can guide the clinical treatment course for gallbladder cancer patients to achieve individualized and effective treatment.

Establishment of patient‐derived organoids for guiding personalized therapies in breast cancer patients

“…Research has shown the impact of interstitial cells on the effectiveness of drugs, especially immune checkpoint inhibitors, and vascular-targeted drugs. 41 It has now been shown that organoids can retain TILs to some extent and for longer periods when stimulated by factors such as IL-2. In the short term, they may be able to replicate the killing effects of drugs such as immune checkpoints.…”

“…One of the limitations of organoid models is the some lack of a cancer microenvironment, which comprises immune cells, fibroblasts, and blood vessels. Research has shown the impact of interstitial cells on the effectiveness of drugs, especially immune checkpoint inhibitors, and vascular‐targeted drugs 41 . It has now been shown that organoids can retain TILs to some extent and for longer periods when stimulated by factors such as IL‐2.…”

Combination of multiple omics techniques for a personalized therapy or treatment selection

“…Indeed, the time length required for their establishment is an obstacle to their implementation for high risk patients and highly aggressive tumors. Despite that, a combination of organoid and PDX was successfully used for personalized therapy selection for a patient with gallbladder cancer ( 149 ). Similarly, for a patient with an urothelial bladder cancer with HRAS mutation, a combination of scRNAseq and PDX identified an upregulation of PD-L1 on chemoresistant cells, thus leading to the treatment of this patient with the anti PD-L1 Ab atezolizumab ( 150 ).…”