Orthotopic Patient-Derived Xenografts of Pediatric Solid Tumors
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ABSTRACT:
PROVIDER: EGAS00001002528 | EGA |
REPOSITORIES: EGA
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Project description:Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for the development of dedicated drug development programs, and this disease is too rare and heterogeneous to gather enough children into a clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas, 1 transitional liver cancer tumor, 1 hepatocellular carcinoma and two rhabdoid tumors. SNP array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors, and recapitulates well the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha-fetoprotein (AFP), low rate of necrosis/fibrosis after treatment and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these combinations, irinotecan/temozolomide induced strong tumor regression in the transitional liver cancer tumor model and on a model derived from AFP-negative relapsing HB. These results provide promising evidence that this preclinical platform can strongly contribute to accelerate the identification and diversification of anti-cancer treatment for aggressive subtypes of pediatric liver cancer.
2016-06-03 | GSE76100 | GEO
Project description:Osteosarcoma (OS) and Ewing’s sarcoma (EW) are the two most common pediatric solid tumors, after brain tumors. Multimodal treatments have significantly improved prognosis in localized disease but outcome is still poor in metastatic patients, for whom therapeutic options are often inadequate. Preclinical drug testing to identify promising treatment options that match the molecular make-up of these tumors is hampered by the lack of appropriate and molecularly well-characterized patient-derived models. To address this need, a panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected OS and EW tumors in NSG mice. Tumors were re-transplanted to next mice generations and fragments were collected for histopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least three passages. To evaluate the similarity of the model with primary tumor, we performed a global gene expression profiling and tissue microarrays (TMA), to assess tumor specific biomarkers on tissues from OS/EW tumors and their PDXs (1st and 3rd passage). Moreover, we verified the feasibility of these models for preclinical drug testing. We implanted 61 OS and 29 EW samples: 14/38 (37%) primary OS and 9/23 (39%) OS lung metastases successfully engrafted; while among EW, 5/26 (19%) primary samples and 1/3 (33%) metastases were established. Comparison between patient samples and PDXs, highlighted that histology and genetic characteristics of PDXs were stable and maintained over passages. In particular, correlative analysis between OS and EW samples and their PDXs was extremely high (Pearson’s r range r=0.94-0.96), while patient-derived primary cultures displayed reduced correlation with human samples (r=0.90-0.93), indicating that in vitro adaptation superimpose molecular alterations that create genetic diversion from original tumors. No significant differentially expressed gene profile was observed from the comparison between EW samples and PDXs (fold change > 2, adjusted p <0.05 at paired t-test). In OS, the comparison between OS patient-derived tumors and PDX indicated differences in 397 genes, mostly belonging to immune system functional category. This is in line with the idea that human immune cells are gradually replaced by murine counterparts upon engraftment in the mouse. As proof-of concept, two EW PDX and one OS PDX have been treated with conventional and innovated drugs to test their value in terms of drug-sensitivity prediction. Overall, our study indicated that PDX models maintained the histological and genetic markers of the tumor samples and represent reliable models to test sensitivity to novel drug associations.
2019-08-27 | E-MTAB-7568 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma has a very poor prognosis, and new therapies and preclinical models are urgently needed. We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), and integrated these to create 13 matched trios, as systematic models for this cancer. Orthotopic implantation (OI) of PDCLs showed tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDX and OI-PDX with passaged tumors showed that histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. Comparing gene expression in PDCLs, ectopic tumors, and OI tumors, CXCR4 and CXCL12 genes were specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. These patient-derived tumor models provide useful tools for preclinical research into pancreatic ductal adenocarcinoma. We performed comprehensive gene expression profiling of 13 pancreatic cancer cell lines, 14 CDX and 14 PDX tumors by Affymetrix Gene Chip HG-U133Plus2.0.
2022-02-16 | GSE157494 | GEO
Project description:Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers and to evaluate novel therapeutics, as they reflect clinical cancers more closely than established tumor cell lines. With >100 PDXs established from resected non-small cell lung carcinomas (NSCLC), we reported previously that xenograftability correlates significantly with poorer patient prognosis. In this study, genomic, transcriptomic, and proteomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with cell lines, using publicly available data on the latter. A higher number of somatic alterations among 865 frequently altered genes in the PDX tumors was associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by a lower number of alterations; this was validated with the TCGA lung cancer patient dataset (HR=0.28, p=0.000022). These passenger-like alterations, identified in PDXs, link cell-cell signaling and adhesion to patient prognosis. Total RNAs from xenograftswere amplified by DASL kit and hybridized to Illumina HT12v4 chip
2016-10-26 | E-GEOD-68929 | biostudies-arrayexpress
Project description:Purpose: Most High-Grade Ovarian Carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain frequently CBP-sensitive and acquire resistance after several CBP cycles. We developed Patient-Derived Xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. Experimental Design: We generated PDX models from CBP-sensitive HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs upon repeated CBP treatment. Tumors were characterized transcriptome levels by Affymetrix microarrays. Results: All PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained non-proliferating tumor cells clusters embedded in a fibrotic mesh. This was absent in CBP-resistant tumors. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of cell cycle and proliferation and upregulation of interferon response and epithelial–mesenchymal transition. This gene expression pattern resembled that seen in embryonal diapause and ‘drug-tolerant persister’ states. Residual and acquired-resistance tumors share the overexpression of three genes – CEACAM6, CRYAB, and SOX2. Conclusions: In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB and SOX2, a signature also associated with acquired resistance and poor patient prognosis
2022-03-16 | GSE198701 | GEO
Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.
2019-12-31 | GSE142767 | GEO
Project description:7 breast cancer patient-derived xenografts (PDXs, 3 tumors per PDX line) labeled with TMT10 and analyzed by LC-MS.
2017-03-23 | MSV000080670 | MassIVE
Project description:Glioma study (gene expression and CGH): Brain tumours are the most common solid tumors in children and have the highest mortality rate of all solid pediatric tumours. Despite advances in multimodality therapy, children with high-grade gliomas invariably have an Overall Survival (OS) around 20% at 5 years. There is growing evidence that the biological knowledge and the histo-prognostic classifications used for the management of adult HGG may not fully apply to children. Interobserver variability and specificity of pediatric tumors with respect to the World Health Organization (WHO) classification have lead to a high rate of misclassification in multi-institutional studies. From 90 biopsies of children with HGG (High Grade Glioma), comprising 37 DIPG (Diffuse Infiltrating Pontine Glioma), 73 extracted RNA have been hybrized on Agilent 4x44K GE arrays and 71 extracted DNA have been hybrized on Agilent 44K and 4x44K CGH arrays. The dataset contains raw data files from Feature Extraction. Genomic data were jointly analysed with clinical and histological data comprising: date_of_diagnosis, date_of_last_news, WHO_grade, deceased_at_median_survival_time, deceased_at_2years, localization of the tumour in brain, gadolinium_T1_inf_T2. A specific analysis was performed on DIPG.
2012-02-22 | E-TABM-1107 | biostudies-arrayexpress
Project description:We established 70 subcutaneous PDX models from 16 different pediatric solid tumor subtypes and applied whole-exome sequencing (WES), whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) to both PDX, matched patient tumor (PT) and germline samples. PDXs can generally recapitulate the genomic and transcriptomic features of their matched PT. However, we found a high somatic mutation discrepancy between PDXs and paired PTs in some cases and showed evidence of clonal selection.
| EGAS00001006710 | EGA
Project description:The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy across a population, but also study crucial aspects of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. The pathways most significantly altered included Protein Kinase A signaling, GNRH signaling, and sphingosine-1-phosphate signaling. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer 6 pairs of Patient-Derived Xenografts (PDX) were ananlyzed using RNA-seq for a total of 12 samples. Each pair consists of a treated and untreated PDX of ovarian cancer. Treated Ovarian cancer PDXs were treated with 4 weeks of a combination of carboplatin and taxol. RNA was isolated and converted to cDNA. RNA-seq was conductred on the Illumina HiSeq 2000 with 50 bp paired end sequencing
2015-06-17 | E-GEOD-58586 | biostudies-arrayexpress