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PubMed | Gustave Roussy Cancer Campus, Marie Lannelongue Hospital, Autonomous University of Barcelona, Institute Hospital del Mar Investigacions Mediques IMIM and 5 more.
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2016

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 dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II 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 (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors. Cytogenetic 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 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, the irinotecan/temozolomide combination induced strong tumor regression in the TCLT and in a model derived from an AFP-negative relapsing HB.These results provide evidence that PLC-PDX preclinical platform can strongly contribute to accelerate the identification and diversification of anticancer treatment for aggressive subtypes of pediatric liver cancer. (Hepatology 2016;64:1121-1135).

Cairo S.,XenTech | Armengol C.,CIBER ISCIII | Buendia M.A.,Institute Pasteur Paris
Frontiers in Bioscience - Elite | Year: 2012

Hepatoblastoma (HB) is the most common type of pediatric liver cancer. This tumor is thought to derive from hepatic progenitor cells that are arrested at various stages of liver development, as illustrated by a variety of histologic subtypes. Recent genomic studies have led to better understand the molecular pathogenesis of HB, to point out the crucial roles of the Wnt Myc signaling pathways in malignant transformation of liver progenitor cells. Molecular classification of HB based on genomewide studies, as well as identification of reliable diagnostic prognostic markers, open the way to the development of new personalized targeted therapies for the management of aggressive lethal childhood tumors.

Cairo S.,XenTech | Buendia M.A.,University Paris - Sud
Journal of Hepatology | Year: 2012

Hepatocyte nuclear factor 4a (HNF4a) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4a initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that,once this circuit is activated, it maintains suppression of HNF4a and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4a circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

PubMed | National Veterinary School of Alfort, Institute Of Recherches Servier, XenTech and University Pierre and Marie Curie
Type: Journal Article | Journal: British journal of cancer | Year: 2016

Oestrogen receptor-negative (ER-) breast cancer is intrinsically sensitive to chemotherapy. However, tumour response is often incomplete, and relapse occurs with high frequency. The aim of this work was to analyse the molecular characteristics of residual tumours and early response to chemotherapy in patient-derived xenografts (PDXs) of breast cancer.Gene and protein expression profiles were analysed in a panel of ER- breast cancer PDXs before and after chemotherapy treatment. Tumour and stromal interferon-gamma expression was measured in xenografts lysates by human and mouse cytokine arrays, respectively.The analysis of residual tumour cells in chemo-responder PDX revealed a strong overexpression of IFN-inducible genes, induced early after AC treatment and associated with increased STAT1 phosphorylation, DNA-damage and apoptosis. No increase in IFN-inducible gene expression was observed in chemo-resistant PDXs upon chemotherapy. Overexpression of IFN-related genes was associated with human IFN- secretion by tumour cells.Treatment-induced activation of the IFN/STAT1 pathway in tumour cells is associated with chemotherapy response in ER- breast cancer. Further validations in prospective clinical trials will aim to evaluate the usefulness of this signature to assist therapeutic strategies in the clinical setting.

Eichenmuller M.,Ludwig Maximilians University of Munich | Trippel F.,Ludwig Maximilians University of Munich | Kreuder M.,Ludwig Maximilians University of Munich | Beck A.,Ludwig Maximilians University of Munich | And 10 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Hepatoblastoma (HB) is the most common childhood liver cancer and occasionally presents with histological and clinical features reminiscent of hepatocellular carcinoma (HCC). Identification of molecular mechanisms that drive the neoplastic continuation towards more aggressive HCC phenotypes may help to guide the new stage of targeted therapies. Methods We performed comprehensive studies on genetic and chromosomal alterations as well as candidate gene function and their clinical relevance. Results Whole-exome sequencing identified HB as a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor NFE2L2 (2/15 cases). Their HCC-like progenies share the common CTNNB1 mutation, but additionally exhibit a significantly increased mutation number and chromosomal instability due to deletions of the genome guardians RAD17 and TP53, accompanied by telomerase reverse-transcriptase (TERT) promoter mutations. Targeted genotyping of 33 primary tumours and cell lines revealed CTNNB1, NFE2L2, and TERT mutations in 72.5%, 9.8%, and 5.9% of cases, respectively. All NFE2L2 mutations affected residues of the NFE2L2 protein that are recognized by the KEAP1/CUL3 complex for proteasomal degradation. Consequently, cells transfected with mutant NFE2L2 were insensitive to KEAP1-mediated downregulation of NFE2L2 signalling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumours was significantly associated with metastasis, vascular invasion, the adverse prognostic C2 gene signature, as well as poor outcome. Conclusions Our study demonstrates the importance of CTNNB1 mutations and NFE2L2-KEAP1 pathway activation in HB development and defines loss of genomic stability and TERT promoter mutations as prominent characteristics of aggressive HB with HCC features. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PubMed | Unite dHistopathologie humaine et modeles animaux., Institute Pasteur Paris, RIKEN, XenTech and Telethon Institute of Genetics and Medicine
Type: Journal Article | Journal: Carcinogenesis | Year: 2016

Multidrug resistance 2 (Mdr2), also called adenosine triphosphate-binding cassette B4 (ABCB4), is the transporter of phosphatidylcholine (PC) at the canalicular membrane of mouse hepatocytes, which plays an essential role for bile formation. Mutations in human homologue MDR3 are associated with several liver diseases. Knockout of Mdr2 results in hepatic inflammation, liver fibrosis and hepatocellular carcinoma (HCC). Whereas the pathogenesis in Mdr2 (-/-) mice has been largely attributed to the toxicity of bile acids due to the absence of PC in the bile, the question of whether Mdr2 deficiency per se perturbs biological functions in the cell has been poorly addressed. As Mdr2 is expressed in many cell types, we used mouse embryonic fibroblasts (MEF) derived from Mdr2 (-/-) embryos to show that deficiency of Mdr2 increases reactive oxygen species accumulation, lipid peroxidation and DNA damage. We found that Mdr2 (-/-) MEFs undergo spontaneous transformation and that Mdr2 (-/-) mice are more susceptible to chemical carcinogen-induced intestinal tumorigenesis. Microarray analysis in Mdr2-/- MEFs and cap analysis of gene expression in Mdr2 (-/-) HCCs revealed extensively deregulated genes involved in oxidation reduction, fatty acid metabolism and lipid biosynthesis. Our findings imply a close link between Mdr2 (-/-) -associated tumorigenesis and perturbation of these biological processes and suggest potential extrahepatic functions of Mdr2/MDR3.

Miltenyi Biotec GmbH and Xentech | Date: 2015-10-07

The present invention provides the use of the biomarkers SSEA4 and/or ST3GAL2 for assessing the outcome for chemotherapeutic treatment of a cancer in an individual and methods thereof.

The invention relates generally to the field of cancer prognosis and treatment. More particularly, the present invention relates to methods and compositions that utilize a particular panel of gene products (biomarkers) and their differential expression patterns (expression signatures), wherein the expression patterns correlate with responsiveness, or lack thereof, to chemotherapy treatment. The invention is based on the identification of a specific set of biomarkers that are differentially expressed in chemotherapy-treated tumors and which are useful in predicting the likelihood of a therapeutic response, including residual disease persistence and subsequent tumor recurrence in cancer patients receiving chemotherapy. The gene panel is also useful in designing specific adjuvant modalities with improved therapeutic efficiency. Also disclosed are methods for characterizing tumors according to expression of the biomarkers described herein.

PubMed | University of Paris Descartes and XenTech
Type: | Journal: Oncotarget | Year: 2016

Activation of the IFN/STAT1 pathway is closely associated with drug response and recurrence of breast cancer treated by chemotherapy. The aim of the current study was to elucidate the molecular mechanisms involved upstream and downstream of this pathway in order to identify distinct entities that might be manipulated to improve treatment efficacy. Four breast cancer cell lines (T-47D, MCF7, MDA-MB-231 and HBCx-19 established from the eponymous PDX) were treated in vitro with mafosfamide, a DNA damage inducer. In two of these cell lines (MCF7 and HBCx-19), genotoxic treatment upregulated type I IFN expression leading to paracrine activation of IFN/STAT1 signaling pathway after 6-8 days. We show that STING, a well-characterized inducer of IFN in immune cells, is rapidly triggered in MCF7 cells under genotoxic stress and forms nuclear foci that co-localize with phosphorylated IRF-3 and H2AX. STING silencing abrogated chemotherapy-induced type I IFN production and signaling and potentiated genotoxic treatment efficacy as it promoted cell death extent and delayed cell colony regrowth. Similar results were obtained after silencing PARP12, one selected gene of the IFN/STAT1 pathway fingerprint. In summary, this study provides the first demonstration of STING activation in breast cancer cells. Our data suggest that genotoxic-induced, STING-mediated type I IFN signaling is a cell-intrinsic mechanism of breast cancer cell survival and regrowth.

Xentech | Date: 2010-03-02

[ Pharmaceutical and veterinary preparations in cancer treatment and oncology; Sanitary preparations for medical purposes; Dietetic foods adapted for medical use; Dietetic sugar for medical use; Pharmaceuticals in the form of lipids for use in the treatment of cancer and for oncological treatments; Plasters for medical purposes in cancer treatment and oncology, materials for dressings, namely, medical dressings; Disinfectants for hygiene purposes in cancer treatment and oncology; Medicated bath preparations in cancer treatment and oncology; Sanitary pads, pants and towels in cancer treatment and oncology; Chemical preparations for medical and pharmaceutical use in cancer treatment and oncology; Sugar for medical use in cancer treatment and oncology ]. Research in cancer treatment and oncology provided by engineers; Pharmaceutical product evaluation in the field of cancer treatment and oncology provided by engineers; [ Design and development of computer hardware and software; ] Research and development of new products for third parties; Research and development of new products for third parties in the field of preclinical oncology and cancer treatment; [ Architecture consultation and design; Design, installation, maintenance, updating and rental of software; Computer programming; Computer consultancy services; Conversion of computer programs and data other than physical conversion; Conversion of documents from a physical to an electronic medium; Graphic arts design services; Industrial design; Authenticating works of art; ] Scientific research for medical purposes. [ Medical services; Veterinary services; Hygienic and beauty care for human beings and animals; Healthcare; Medical assistance; Plastic surgery; Hospitals; Nursing homes with medical care ].

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