Creating Matched In vivo/In vitro Patient-Derived Model Pairs of PDX and PDX-Derived Organoids for Cancer Pharmacology Research

Xu, Xiaoxi; Shang, Limei; Wang, Philip; Zhou, Jun; Ouyang, Xuesong; Zheng, Meiling; Mao, Binchen; Likun, Zhang; Chen, Bonnie; Wang, Jingjing; Chen, Jing; Qian, Wubin; Guo, Sheng; Huang, Yujun; Li, Qi-Xiang

doi:10.3791/61382

Cited by 7 publications

(21 citation statements)

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“…Pancreatic ductal adenocarcinoma PDXOs displayed similar drug sensitivity and glycan profiles to their PDX counterparts ( 47 ). A protocol for deriving a PDXO from a PDX was recently published by Xu and colleagues, and the established colorectal cancer PDXO displayed similar drug sensitivity and gene expression profiles to its parent PDX ( 48 ). Although this higher throughput method captures the drug response profiles of PDX counterparts, the time required establish both a PDX and PDO may pose a limit for implementation in the precision oncology realm.…”

Section: Patient-derived Xenograftsmentioning

confidence: 99%

Functional Drug Screening in the Era of Precision Medicine

2022

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The focus of precision medicine is providing the right treatment to each unique patient. This scientific movement has incited monumental advances in oncology including the approval of effective, targeted agnostic therapies. Yet, precision oncology has focused largely on genomics in the treatment decision making process, and several recent clinical trials demonstrate that genomics is not the only variable to be considered. Drug screening in three dimensional (3D) models, including patient derived organoids, organs on a chip, xenografts, and 3D-bioprinted models provide a functional medicine perspective and necessary complement to genomic testing. In this review, we discuss the practicality of various 3D drug screening models and each model’s ability to capture the patient’s tumor microenvironment. We highlight the potential for enhancing precision medicine that personalized functional drug testing holds in combination with genomic testing and emerging mathematical models.

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Section: Patient-derived Xenograftsmentioning

confidence: 99%

Functional Drug Screening in the Era of Precision Medicine

2022

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“…In comparison, organoid screening is more complex and has a lower throughput than the standard 2D HTS due to the 3D culturing methods with Matrigel and the inclusion of morphology monitoring/imaging. Nonetheless, organoid HTS can be nearly as robust and reproducible as 2D cell culture screens with established endpoint readouts such as cell viability and standardization (Xu et al., 2021).…”

Section: Limitation Comparison With Other Preclinical Systemsmentioning

confidence: 99%

“…We and others have successfully developed PDXOs from PDXs of various cancer types, including NSCLC (non‐small cell lung carcinoma), CRC (colorectal carcinoma), gastric carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, hepatocellular carcinoma, etc ., Table 1 (Arena et al., 2020; Beshiri et al., 2018; Corso et al., 2019; Guillen et al., 2022; Lee et al., 2020; Schütte et al., 2017; Shi et al., 2020; Xu et al., 2021). PDX tumors harvested from mice are enzymatically digested and mechanically disrupted to isolate cells embedded in Matrigel to establish domes in an organoid culture (Xu et al., 2021). PDXOs can be established with high efficiency from fresh or frozen tissue and further cryopreserved and resuscitated to enable biobanking and in vitro expansion.…”

Section: Establishing a Biobank Of Matched Organoid And Pdx Modelsmentioning

confidence: 99%

“…Organoid HTS is a robust assay system for accuracy, precision, and reliability with a very high signal‐to‐noise ratio, precision for intra‐plate readouts as indicated by a high z′‐prime value, and high inter‐plate reproducibility. In our lab, PDXO drug screening is automated, highly reproducible, robust, efficient, and ideally positioned to fill the gap between 2D drug screening and PDX MCTs (Xu et al., 2021). PDXOs can be selected based on the model information curated in an online organoid database, which complements the PDX online database.…”

Section: Application Of Pdxo To Drug Developmentmentioning

confidence: 99%

“…Screens are conducted similarly to a standard 2D 384‐well format screen with positive (staurosporine or appropriate standard of care relative to indication/subtype) and negative (vehicle) controls on each plate. Test agents are incubated with the organoids for 5‐7 days with a CellTiter‐Glo (CTG) viability readout or morphology assessment as endpoints (Xu et al., 2021). Assay duration is dependent on the model growth kinetics at a specific seeding density; for example, for the prostate cancer PDXO, assay duration was 2 weeks with seeding of 4000 cells/well (Beshiri et al., 2018).…”

Section: Application Of Pdxo To Drug Developmentmentioning

confidence: 99%

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Translational and Clinical Relevance of PDX‐Derived Organoid Models in Oncology Drug Discovery and Development

Kumari¹,

Li³

2022

Current Protocols

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Patient‐derived cancer disease models conserve many key features of the original human cancers, potentially allowing higher predictive power than traditional cell line models. Accordingly, in vivo patient‐derived xenografts (PDX) are frequently utilized in preclinical and translational oncology studies as patient surrogates for population‐based screens (“mouse clinical trials”), for which large PDX biobanks have been generated over the last decade from various cancer types. In vitro patient‐derived organoids (PDO) have recently emerged as a disruptive technology, enabling early “patient in a dish” clinical trials. Like PDX, PDOs retain the histology/genomics of the original tumor and are highly predictive of the clinical response. Organoids derived from adult stem cells (ASC) in patient tissue can function as mini‐organs. They have greater advantages over other 3D in vitro systems, making them highly predictive, reliable, and consistent in vitro models. Large biobanks enable the adoption of organoids in early drug screening and patient selection. PDX biobanks, as a source of human material, have been used to create 3D in vitro screens, but with limitations. However, creating organoids from the ASCs residing in PDXs has been successfully used as a rapid and cost‐effective way to enable higher throughput in vitro screens and generate matched in vitro/in vivo model pairs that retain genomic, histopathological, and pharmacology profiles. This overview summarizes the generation of matched in vitro/in vivo models from patient material, the advantages over other systems, and the applications to drug discovery. © 2022 Wiley Periodicals LLC.

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A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology

Kumari²,

Zhou

et al. 2023

PLoS ONE

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Patient-derived tumor xenograft (PDX)/organoid (PDO), driven by cancer stem cells (CSC), are considered the most predictive models for translational oncology. Large PDX collections reflective of patient populations have been created and used extensively to test various investigational therapies, including population-trials as surrogate subjects in vivo. PDOs are recognized as in vitro surrogates for patients amenable for high-throughput screening (HTS). We have built a biobank of carcinoma PDX-derived organoids (PDXOs) by converting an existing PDX library and confirmed high degree of similarities between PDXOs and parental PDXs in genomics, histopathology and pharmacology, suggesting “biological equivalence or interchangeability” between the two. Here we demonstrate the applications of PDXO biobank for HTS “matrix” screening for both lead compounds and indications, immune cell co-cultures for immune-therapies and engineering enables in vitro/in vivo imaging. This large biobank of >550 matched pairs of PDXs/PDXOs across different cancers could become powerful tools for the future cancer drug discovery.

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Creating Matched In vivo/In vitro Patient-Derived Model Pairs of PDX and PDX-Derived Organoids for Cancer Pharmacology Research

Cited by 7 publications

References 0 publications

Functional Drug Screening in the Era of Precision Medicine

Functional Drug Screening in the Era of Precision Medicine

Translational and Clinical Relevance of PDX‐Derived Organoid Models in Oncology Drug Discovery and Development

A living biobank of matched pairs of patient-derived xenografts and organoids for cancer pharmacology

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