Center Regional Of Lutte Contre Le Cancer

Rennes, France

Center Regional Of Lutte Contre Le Cancer

Rennes, France
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Laboratoire Francais Du Fractionnement Des Biotechnologies, Center Regional Of Lutte Contre Le Cancer and Montpellier University | Date: 2016-10-25

The invention relates to novel pharmaceutical compositions including, as active ingredient, an antibody binding the human anti-Mllerian hormone type II receptor (AMHR-II) and an anticancer agent, as well as the therapeutic applications of these compositions.


Weyland M.,French Institute of Health and Medical Research | Weyland M.,University of Angers | Manero F.,French Institute of Health and Medical Research | Manero F.,University of Angers | And 18 more authors.
Journal of Controlled Release | Year: 2011

Taking advantage from the development of SV30, a new analogue of the pro-apoptotic molecule HA14-1, the aim of this study was to functionally evaluate SV30 and to develop safe nanocarriers for its administration. By using an inversion phase process, 57 nm organic solvent-free lipid nanocapsules loaded with SV30 (SV30-LNCs) were formulated. Biological performance of SV30 and SV30-LNCs were evaluated on F98 cells that express Bax and Bcl-2, through survival assays, HPLC, flow cytometry, confocal microscopy and spectral imaging. We observed that SV30 alone or in combination with paclitaxel, etoposide or beam radiation could trigger cell death in a similar fashion to HA14-1. Although partially blocked by Z-VAD-fmk, this effect was coincident to caspase-3 activation. Hence, we established that SV30-LNCs improved SV30 biological activity together with a potentiation of the mitochondrial membrane potential decrease. Interestingly, flow cytometry and confocal analysis indicated that SV30 itself conferred to LNCs improved mitochondrial targeting skills that may present a great interest toward the development of mitochondria targeted nanomedicines. © 2010 Elsevier B.V.


Allard E.,French Institute of Health and Medical Research | Jarnet D.,Center Regional Of Lutte Contre Le Cancer | Vessieres A.,École Nationale Supérieure de Chimie de Paris | Vinchon-Petit S.,French Institute of Health and Medical Research | And 4 more authors.
Pharmaceutical Research | Year: 2010

Purpose: The goal of the present study was to evaluate the efficacy of a new organometallic drug, ferrociphenol (Fc-diOH), in combination with external radiotherapy in intracerebral 9L glioma model. We tested the hypothesis that the combination of external radiotherapy with Fc-diOH could potentiate the action of this drug. Methods: 9L cells were treated with Fc-diOH-LNCs (from 0.01 to 1μmol/L) and irradiated with external radiotherapy (from 2 to 40 Gy). In vivo assessment was evaluated by the inoculation of 9L cells in Fisher rats. Chemotherapy with Fc-diOH-LNCs (0.36 mg/rat) was administered by means of convection-enhanced delivery (CED), and the treatment was followed by three irradiations of 6 Gy doses (total dose=18 Gy). Results: In vitro evaluations evidenced that a combined treatment with Fc-diOH-LNCs and irradiations showed synergistic antitumor activity on 9L cells. Combining cerebral irradiation with CED of Fc-diOH-LNCs led to a significantly longer survival and the existence of long-term survivors compared to Fc-diOH-LNCs-treated animals (p<0.0001) and to the group treated with blank LNCs+radiotherapy (p=0.0079). Conclusion: The synergistic effect between ferrociphenol-loaded LNCs and radiotherapy was due to a closely oxidative relationship. Upon these considerations, Fc-diOH-LNCs appear to be an efficient radiosensitive anticancer drug delivery system. © 2009 Springer Science+Business Media, LLC.


Sarrabayrouse G.,French Institute of Health and Medical Research | Corvaisier M.,French Institute of Health and Medical Research | Ouisse L.-H.,French Institute of Health and Medical Research | Bossard C.,French Institute of Health and Medical Research | And 8 more authors.
International Journal of Cancer | Year: 2011

High level of T-cell infiltration in colorectal carcinomas (CRCs) is a good prognostic indicator, but the tumor reactivity of this infiltrate (tumor infiltrating lymphocytes [TIL]) is poorly documented. This study examined the presence, phenotype and functional features of tumor-reactive lymphocytes in human CRC. Freshly dissociated TIL and T cell lines were isolated from CRC samples and from some paired normal colonic mucosa. Four tumor cell lines were obtained. Autologous tumor reactivity of CRC TIL and tumor-reactive cell features were analyzed. We demonstrate the presence among CRC TIL of variable fractions (up to 18%) of double positive CD4+CD8αβ + (DP) αβ T cells. Interestingly, a high proportion (16-20%) of this TIL subset displayed tumor reactivity, whilst this was the case for no or few single positive TIL. Low levels of DP TIL were found in most CRC samples and in normal colonic mucosa, but these cells were higher in metastatic CRC. Furthermore, we showed that DP TIL were polyclonal, restricted by HLA class-I, proliferated poorly and secreted higher amounts of IL-4 and IL-13 than single positive T cells, on cognate or CD3 stimulation. DP CRC TIL also expressed CD103, confirming their mucosal origin. Increased frequencies of tumor-reactive DP TIL in metastatic CRC suggest that these cells play a role in the metastatic process of this cancer. Based on their high secretion of IL-4 and IL-13 and on previously described roles of these cytokines in cancers, we postulate that DP TIL could favor CRC growth or metastasis and/or downmodulate immune responses to these tumors. © 2010 UICC.


Sulpice L.,French Institute of Health and Medical Research | Sulpice L.,University of Rennes 1 | Sulpice L.,Rennes University Hospital Center | Rayar M.,University of Rennes 1 | And 22 more authors.
Hepatology | Year: 2013

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well-established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFβ2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. © 2013 by the American Association for the Study of Liver Diseases.


Vinchon-Petit S.,French Institute of Health and Medical Research | Jarnet D.,Center Regional Of Lutte Contre Le Cancer | Paillard A.,French Institute of Health and Medical Research | Benoit J.-P.,French Institute of Health and Medical Research | And 3 more authors.
Journal of Neuro-Oncology | Year: 2010

The objective of the present study was to investigate the interest of convection-enhanced delivery (CED) for the administration of a nanocarrier-based radiosensitizing chemotherapy in the rat brain. Pursuing on newly developed lipid nanocapsules (LNC) that can be internalised within brain tumour cells, we studied their intracerebral distribution when labelled with fluorescent Nile red (NR). As paclitaxel (Px) represents an interesting radiosensitiser, we also evaluated the potential radiosensitising effects of Px-loaded LNC administered through CED in the 9L intracranial rat glioblastoma model. The distribution study demonstrated that CED injection of NR-loaded LNC (NR-LNC) improved significantly the volume of distribution of NR when matched with simple injection (by about 150 fold). It also reveals that the LNC perfusion of a whole tumour forming area inside the CNS (6 days after implantation of 103 9L cells) is achievable through CED injection, whilst preserving the ability of LNC to reach the intracellular space of encountered tumour cells. Having established an animal model of encephalic irradiation close to the clinic (18 Gray in three fractions of six Gray at days 8, 11 and 14 after 9L cell implantation) we proved the feasibility of the combination of CED for the administration of drug-loaded LNC with external beam therapy. Although a single CED injection of Px-LNC at low Px dose (375 lg/kg of bodyweight) gave the best median survival (twice that of untreated controls), it underlines the need for optimisation. Hence, the possibility of grafting recognition moieties onto the LNC surface combined to their biocompatibility must be beneficial. © 2009 Springer Science+Business Media, LLC.


Rayar M.,University of Rennes 1 | Sulpice L.,University of Rennes 1 | Edeline J.,Center Regional Of Lutte Contre Le Cancer | Garin E.,Center Regional Of Lutte Contre Le Cancer | And 4 more authors.
Annals of Surgical Oncology | Year: 2015

Purpose: To evaluate the downstaging efficacy of yttrium-90 radioembolization (Ytt-90)-associated with chemotherapy and the results of surgery for initially unresectable huge intrahepatic cholangiocarcinoma (ICC). Methods: Between January 2008 and October 2013, unresectable ICC were treated with chemotherapy and Ytt-90. Patients with unique tumors localized to noncirrhotic livers and without extrahepatic metastasis were considered to be potentially resectable and were evaluated every 2 months for possible secondary resection. Results: Forty-five patients were treated for unresectable ICCs; ten had potentially resectable tumors, and eight underwent surgery. Initial unresectability was due to the involvement of the hepatic veins or portal vein of the future liver remnant in seven and one cases, respectively. Preoperative treatment induced significant decreases in tumor volume (295 vs. 168 ml, p = 0.02) and allowed for R0 resection in all cases. Three patients (37.5 %) had Clavien–Dindo grade three or higher complications, including two postoperative deaths. The median follow-ups were 15.6 [range 4–40.7] months after medical treatment initiation and 7.2 [0.13–36.4] months after surgery. At the end of the study period, five patients were still alive, with one patient still alive 40 months after medical treatment initiation (36.4 months after surgery); two patients experienced recurrences. Conclusions: For initially unresectable huge ICCs, chemotherapy with Ytt-90 radioembolization is an effective downstaging method that allows for secondary resectability. © 2015, Society of Surgical Oncology.


Perol M.,Center Regional Of Lutte Contre Le Cancer
Revue des Maladies Respiratoires Actualites | Year: 2011

First-line treatment of advanced non-small cell lung cancer has considerably evolved during the last decade. Most of new therapeutic options are built around the third generation platin-based chemotherapy, with the introduction of pemetrexed in this first-fline setting or the addition of an antiangiogenic antibody as bevacizumab to chemotherapy for eligible patients. Maintenance treatment strategies for patients with controlled disease after induction platin-based chemotherapy provide significant survival benefit with pemetrexed for non-squamous carcinoma or erlotinib for patients with stabilized disease after induction chemotherapy. Personalized treatments are already available with the introduction of EGFR tyrosine kinase inhibitors as first-line therapy for patients with EGFR mutations. Further progress will probably come from a more personalized therapeutic approach with the discovery of new oncogenic molecular abnormalities as ALK gene rearrangement. © 2011 Société de Pneumologie de Langue Française (SPLF).


Lavergne E.,French Institute of Health and Medical Research | Lavergne E.,University of Rennes 1 | Hendaoui I.,French Institute of Health and Medical Research | Hendaoui I.,University of Rennes 1 | And 16 more authors.
Oncogene | Year: 2011

Constitutive activation of Wnt/Β-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the Β-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the ΔS45 activating mutation in one of the alleles of Β-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced Β-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased [ 3 H]-thymidine (in vitro) or BrdU (in vivo) incorporation, clonogenesis assays, cell cycle analysis and magnetic resonance imaging in living mice. Additionally, V3Nter switches off the Β-catenin target gene expression signature in vivo. Moreover, experiments with Β-catenin allele-targeted cells showed that the ΔS45 Β-catenin allele hampers, but does not abrogate, inhibition of Wnt signaling by SFRP-1 or by the SFRP-like frizzled domain. Finally, neither SFRP-1 nor V3Nter affect Β-catenin signaling in SW480 cells carrying nonfunctional Adenomatous polyposis coli. Thus, SFRP-1 and the SFRP-like molecule V3Nter can inhibit tumor growth of Β-catenin-activated tumor cells in vivo. © 2011 Macmillan Publishers Limited All rights reserved.


Le Maire A.,French Institute of Health and Medical Research | Le Maire A.,French National Center for Scientific Research | Teyssier C.,French Institute of Health and Medical Research | Teyssier C.,French National Center for Scientific Research | And 18 more authors.
Nature Structural and Molecular Biology | Year: 2010

In the absence of ligand, some nuclear receptors, including retinoic acid receptor (RAR), act as transcriptional repressors by recruiting corepressor complexes to target genes. This constitutive repression is crucial in metazoan reproduction, development and homeostasis. However, its specific molecular determinants had remained obscure. Using structural, biochemical and cell-based assays, we show that the basal repressive activity of RAR is conferred by an extended Β-strand that forms an antiparallel Β-sheet with specific corepressor residues. Agonist binding induces a Β-strand-to-α-helix transition that allows for helix H11 formation, which in turn provokes corepressor release, repositioning of helix H12 and coactivator recruitment. Several lines of evidence suggest that this structural switch could be implicated in the intrinsic repressor function of other nuclear receptors. Finally, we report on the molecular mechanism by which inverse agonists strengthen corepressor interaction and enhance gene silencing by RAR. © 2010 Nature America, Inc. All rights reserved.

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