PDX Finder: A portal for patient-derived tumor xenograft model discovery

Conte, Nathalie; Mason, Jeremy; Halmagyi, Csaba; Neuhauser, Steven B.; Mosaku, Abayomi; Yordanova, Galabina; Chatzipli, Aikaterini; Begley, Dale A.; Krupke, Debra M.; Parkinson, Helen; Meehan, Terrence F.; Bult, Carol

doi:10.1093/nar/gky984

Cited by 84 publications

(41 citation statements)

References 18 publications

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“…Our PDOX models are freely available to the scientific community. To facilitate the access to established models, we provide detailed information for the best characterized models via PDXFinder ( https://www.pdxfinder.org/ ) [ 30 ]. New models will be regularly added to the resource with molecular and histopathological characterization.…”

Section: Methodsmentioning

confidence: 99%

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

et al. 2020

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Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

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Section: Methodsmentioning

confidence: 99%

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

et al. 2020

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“…In this work, we describe PCAT, a new resource for childhood cancer PDX models. Previously published portals such as PDX Finder ( 22 ) have a larger repository than PCAT. However, PCAT is distinct in its collection of childhood cancer PDXs.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

PCAT: an integrated portal for genomic and preclinical testing data of pediatric cancer patient-derived xenograft models

Yang¹,

Li²,

Noureen³

et al. 2020

Nucleic Acids Research

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Although cancer is the leading cause of disease-related mortality in children, the relative rarity of pediatric cancers poses a significant challenge for developing novel therapeutics to further improve prognosis. Patient-derived xenograft (PDX) models, which are usually developed from high-risk tumors, are a useful platform to study molecular driver events, identify biomarkers and prioritize therapeutic agents. Here, we develop PDX for Childhood Cancer Therapeutics (PCAT), a new integrated portal for pediatric cancer PDX models. Distinct from previously reported PDX portals, PCAT is focused on pediatric cancer models and provides intuitive interfaces for querying and data mining. The current release comprises 324 models and their associated clinical and genomic data, including gene expression, mutation and copy number alteration. Importantly, PCAT curates preclinical testing results for 68 models and 79 therapeutic agents manually collected from individual agent testing studies published since 2008. To facilitate comparisons of patterns between patient tumors and PDX models, PCAT curates clinical and molecular data of patient tumors from the TARGET project. In addition, PCAT provides access to gene fusions identified in nearly 1000 TARGET samples. PCAT was built using R-shiny and MySQL. The portal can be accessed at http://pcat.zhenglab.info or http://www.pedtranscriptome.org.

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“…Different PDX repositories exist that represent models of various tumors. Conte and colleagues try to accumulate the data into one comprehensive open global catalog of PDX models and their associated datasets that would ease the identification of PDX models relevant to specific cancer research questions [96]. The standard was also developed to unify generation, quality assurance, and use of PDX models, because the processes of creation and characterization of PDX models considerably differed among institutions [97].…”

Section: In Vivo Modelsmentioning

confidence: 99%

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Stulpinas¹,

Imbrasaitė²,

Krestnikova³

et al. 2020

Tumor Progression and Metastasis

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Despite the advancements in biomarker-based personalized cancer therapy, the inadequacy of molecular and genetic profiling in identifying effective drug combinations was defined in most cases. Drug resistance remains a major limitation of the current predictive oncology. Emerging reports indicate that the success of anticancer therapy is usually limited by intratumoral heterogeneity which is not captured by the existing cancer cell biomarker-based approaches. Cell heterogeneity, not only genetic but also phenotypic, is considered to be the root cause of resistance to anticancer treatment, cancer progression, and the presence of cancer stem cells. Therefore, functional testing of live cells representing various cell types within the tumor exposed to potential therapies is needed for identification of effective drug combinations. Here we look at the different existing model systems, including ex vivo models of the patient's tumor cells, 2D/3D in vitro cultures/cocultures, patient-derived cellular organoids, single-cell models, ex vivo tumor platforms containing tumor microenvironment and extracellular matrix, etc., scoping at drug efficacy evaluation and solving the problem of cancer resistance.

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PDX Finder: A portal for patient-derived tumor xenograft model discovery

Cited by 84 publications

References 18 publications

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

PCAT: an integrated portal for genomic and preclinical testing data of pediatric cancer patient-derived xenograft models

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

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