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An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

ABSTRACT: Lack of preclinical patient-derived xenograft cancer models in which to conduct large-scale molecular studies seriously impairs the development of effective personalized therapies. We report here an in vivo concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large-scale RNA-seq analysis to characterize therapeutic-induced changes in gene expression. The model was established to recapitulate triple-negative breast cancer (TNBC) and validated using TNBC standards of care and an investigational therapeutic agent.

SUBMITTER: Jarrosson L

PROVIDER: S-EPMC8608609 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

Jarrosson Loraine L Costechareyre Clélia C Gallix Fanny F Ciré Séverine S Gay Fabien F Imbaud Olivier O Teinturier Romain R Marangoni Elisabetta E Aguéra Karine K Delloye-Bourgeois Céline C Castellani Valérie V

iScience 20211112 12

Lack of preclinical patient-derived xenograft cancer models in which to conduct large-scale molecular studies seriously impairs the development of effective personalized therapies. We report here an <i>in vivo</i> concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large-scale RNA-seq analysis to characterize therapeutic-induced chang ...[more]

PMID: 34849474

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An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

Project description:Lack of preclinical patient-derived xenograft (PDX) cancer models in which to conduct large scale molecular studies seriously impairs the development of effective personalized therapies. We report here on an in vivo concept consisting of implanting human tumor cells in targeted tissues of an avian embryo, delivering therapeutics, evaluating their efficacy by measuring tumors using light sheet confocal microscopy, and conducting large scale RNAseq analysis to characterize therapeutic-induced changes in gene expression. The model was established to recapitulate triple negative breast cancer (TNBC) and validated using TNBC standards of care (SOCs) and an investigational therapeutic agent.

2021-11-17 | GSE172218 | GEO

An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

Project description:An avian embryo patient-derived xenograft model for preclinical studies of human breast cancers.

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Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies.

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A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies.

Project description:Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

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Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies.

Project description:PurposePatient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research.Materials and methodsWe successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues.ResultsPatients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor-overexpressing PDX with clear cell histology (p=0.023).ConclusionPDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

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Preclinical Therapeutic Assessment of a New Chemotherapeutics [Dichloro(4,4'-Bis(2,2,3,3-Tetrafluoropropoxy) Methyl)-2,2'-Bipryridine) Platinum] in an Orthotopic Patient-Derived Xenograft Model of Triple-Negative Breast Cancers.

Project description:Cisplatin is one of the most common therapeutics used in treatments of several types of cancers. To enhance cisplatin lipophilicity and reduce resistance and side effects, a polyfluorinated bipyridine-modified cisplatin analogue, dichloro[4,4'-bis(2,2,3,3-tetrafluoropropoxy)methyl)-2,2'-bipryridine] platinum (TFBPC), was synthesized and therapeutic assessments were performed. TFBPC displayed superior effects in inhibiting the proliferation of several cisplatin-resistant human cancer cell lines, including MDA-MB-231 breast cancers, COLO205 colon cancers and SK-OV-3 ovarian cancers. TFBPC bound to DNA and formed DNA crosslinks that resulted in DNA degradation, triggering the cell death program through the PARP/Bax/Bcl-2 apoptosis and LC3-related autophagy pathway. Moreover, TFBPC significantly inhibited tumor growth in both animal models which include a cell line-derived xenograft model (CDX) of cisplatin-resistant MDA-MB-231, and a patient-derived xenograft (PDX) model of triple-negative breast cancers (TNBCs). Furthermore, the biopsy specimen from TFBPC-treated xenografts revealed decreased expressions of P53, Ki-67 and PD-L1 coupled with higher expression of cleaved caspase 3, suggesting TFBPC treatment was effective and resulted in good prognostic indications. No significant pathological changes were observed in hematological and biochemistry tests in blood and histological examinations from the specimen of major organs. Therefore, TFBPC is a potential candidate for treatments of patients suffering from TNBCs as well as other cisplatin-resistant cancers.

| S-EPMC9031226 | biostudies-literature

A novel patient-derived xenograft model for claudin-low triple-negative breast cancer.

Project description:BACKGROUND:Triple-negative breast cancer (TNBC) subtypes are clinically aggressive and cannot be treated with targeted therapeutics commonly used in other breast cancer subtypes. The claudin-low (CL) molecular subtype of TNBC has high rates of metastases, chemoresistance and recurrence. There exists an urgent need to identify novel therapeutic targets in TNBC; however, existing models utilized in target discovery research are limited. Patient-derived xenograft (PDX) models have emerged as superior models for target discovery experiments because they recapitulate features of patient tumors that are limited by cell-line derived xenograft methods. METHODS:We utilize immunohistochemistry, qRT-PCR and Western Blot to visualize tumor architecture, cellular composition, genomic and protein expressions of a new CL-TNBC PDX model (TU-BcX-2O0). We utilize tissue decellularization techniques to examine extracellular matrix composition of TU-BcX-2O0. RESULTS:Our laboratory successfully established a TNBC PDX tumor, TU-BCX-2O0, which represents a CL-TNBC subtype and maintains this phenotype throughout subsequent passaging. We dissected TU-BCx-2O0 to examine aspects of this complex tumor that can be targeted by developing therapeutics, including the whole and intact breast tumor, specific cell populations within the tumor, and the extracellular matrix. CONCLUSIONS:Here, we characterize a claudin-low TNBC patient-derived xenograft model that can be utilized for therapeutic research studies.

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Exploring a model-based analysis of patient derived xenograft studies in oncology drug development.

Project description:PurposeTo assess whether a model-based analysis increased statistical power over an analysis of final day volumes and provide insights into more efficient patient derived xenograft (PDX) study designs.MethodsTumour xenograft time-series data was extracted from a public PDX drug treatment database. For all 2-arm studies the percent tumour growth inhibition (TGI) at day 14, 21 and 28 was calculated. Treatment effect was analysed using an un-paired, two-tailed t-test (empirical) and a model-based analysis, likelihood ratio-test (LRT). In addition, a simulation study was performed to assess the difference in power between the two data-analysis approaches for PDX or standard cell-line derived xenografts (CDX).ResultsThe model-based analysis had greater statistical power than the empirical approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25% whereas the empirical approach required at least 50% TGI. The simulation study confirmed the findings and highlighted that CDX studies require fewer animals than PDX studies which show the equivalent level of TGI.ConclusionsThe study conducted adds to the growing literature which has shown that a model-based analysis of xenograft data improves statistical power over the common empirical approach. The analysis conducted showed that a model-based approach, based on the first mathematical model of tumour growth, was able to detect smaller size of effect compared to the empirical approach which is common of such studies. A model-based analysis should allow studies to reduce animal use and experiment length providing effective insights into compound anti-tumour activity.

| S-EPMC7847196 | biostudies-literature

A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers.

Project description:Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCAMUT) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2MUT PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2MUT PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCAMUT HGSOC.

| S-EPMC5214535 | biostudies-literature

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