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Patient-derived xenograft models in cancer therapy: technologies and applications.

ABSTRACT: Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.

SUBMITTER: Liu Y

PROVIDER: S-EPMC10097874 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Patient-derived xenograft models in cancer therapy: technologies and applications.

Liu Yihan Y Wu Wantao W Cai Changjing C Zhang Hao H Shen Hong H Han Ying Y

Signal transduction and targeted therapy 20230412 1

Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-o ...[more]

PMID: 37045827

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Project description:BackgroundEndometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models.MethodsHere, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC.ResultsPDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature.ConclusionsEC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Project description:Background and aimsPancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet shown encouraging results in pancreatic cancer possibly because of a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenograft (PDX) models, compare their genetics to the original biopsies, and assess if autologous tumor-infiltrating lymphocytes (TILs) would have antitumoral activity in pancreatic cancer.MethodsWe subcutaneously transplanted tumors from 29 patients into NOG mice to generate PDX models. We established TIL cultures and injected them into PDX mice. We analyzed histology and genetics of biopsies and PDX tumors.ResultsTumor growths were confirmed in 11 of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but because stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than programmed death ligand-1 (PD-L1) were expressed in pancreatic cancers, but PD-L1 was rarely expressed. When it was expressed, it correlated with tumor take in PDX models. One of the 3 tumors that expressed PD-L1 was an adenosquamous cancer, and another had a mismatch repair deficiency. TILs were expanded from 6 tumors and were injected into NOG or human interleukin-2 transgenic-NOG mice carrying PDX tumors. Regression of tumors could be verified in human interleukin-2 transgenic-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model.ConclusionPDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers and to evaluate responses to adoptive cell therapy and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.

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Patient-derived xenograft models in cancer therapy: technologies and applications.

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Patient-derived xenograft models in cancer therapy: technologies and applications.

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