Systematic Establishment of Robustness and Standards in Patient-Derived Xenograft Experiments and Analysis

Evrard, Yvonne A.; Srivastava, Anuj; Randjelović, Jelena; Doroshow, James H.; Dean, Dennis A.; Morris, Jeffrey S.; Chuang, Jeffrey H.

doi:10.1158/0008-5472.can-19-3101

Cited by 48 publications

(49 citation statements)

References 52 publications

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“…As PDX can be passaged without in vitro processing procedures, a PDX model enables the propagation and expansion of human cancers without oblivious genetic transformation of cancer cells over multiple murine generations [49]. Within a PDX model, human cancer can grow in a physiologically relevant cancer microenvironment that mimics the hormone, nutrient, and oxygen levels that are observed in primary human cancer tissues [50]. Thus, a PDX model shows significant advantages over established cancer cell lines in cancer research.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Hong

Lee

Clayton

et al. 2020

J Exp Clin Cancer Res

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Background: The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods: In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in a patient-derived xenograft nude mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination, and immunofluorescence were utilized to evaluate the regulatory signaling pathway. Results: Our research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, the therapeutic effects of genipin in a patient-derived HCC xenograft nude mice model were also demonstrated. Conclusions: In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with the SH2-STAT-3 domain and suppressing the activity of STAT-3. In the future, further research is planned to explore the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

Hong

Lee

Clayton

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…PDXs were shown to be more accurate in predicting treatment responses than common cell lines [46]. Several international initiatives, such as the EurOPDX and PDXNet consortia, now develop and standardize PDXs for preclinical studies [42,72]. However, a recent evaluation of GBM PDXs highlighted drawbacks in retaining chromosomal copy number alterations (CNAs) [7], and it remains to be seen whether they represent a sustainable model for testing precision medicine regimens.…”

Section: Introductionmentioning

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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“…As PDX can be passaged without in vitro processing procedures, PDX model enable the propagation and expansion of human cancers without oblivious genetic transformation of cancer cells over multiple murine generations [43]. Within PDX model, human cancer can grow in physiologically-relevant cancer microenvironment that mimic the hormone, nutrients and oxygen levels that are observed in the primary human cancer tissues [44]. Thus, PDX model shows signi cant advantages over established cancer cell lines in cancer research.…”

Section: Discussionmentioning

confidence: 99%

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

Hong

Lee

Clayton

et al. 2020

Preprint

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Background Signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signalling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment. Methods In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in patient-derived xenograft mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination and immunofluorescence were utilized to evaluate the regulatory signalling pathway. Results Our research have demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may attribute to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, we also demonstrated the therapeutic effects of genipin in patient-derived HCC xenograft mice model.Conclusion In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with SH2-STAT-3 domain and suppressing the activity of STAT-3. In future study, further research are expected for exploring the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

show abstract

Systematic Establishment of Robustness and Standards in Patient-Derived Xenograft Experiments and Analysis

Cited by 48 publications

References 52 publications

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

RETRACTED ARTICLE: Genipin suppression of growth and metastasis in hepatocellular carcinoma through blocking activation of STAT-3

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

Genipin Suppresses Growth and Metastasis in Hepatocellular Carcinoma Through Blocking Activation of STAT-3

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