Boulogne-Billancourt, France
Boulogne-Billancourt, France

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Astorgues-Xerri L.,Oncology Therapeutic Development | Riveiro M.E.,Oncology Therapeutic Development | Tijeras-Raballand A.,AAREC Filia Research | Serova M.,AAREC Filia Research | And 4 more authors.
Cancer Treatment Reviews | Year: 2014

Galectins belong to a family of carbohydrate-binding proteins with an affinity for β-galactosides. Galectin-1 is differentially expressed by various normal and pathologic tissues and displays a wide range of biological activities. In oncology, galectin-1 plays a pivotal role in tumor growth and in the multistep process of invasion, angiogenesis, and metastasis. Evidence indicates that galectin-1 exerts a variety of functions at different steps of tumor progression. Moreover, it has been demonstrated that galectin-1 cellular localization and galectin-1 binding partners depend on tumor localization and stage. Recently, galectin-1 overexpression has been extensively documented in several tumor types and/or in the stroma of cancer cells. Its expression is thought to reflect tumor aggressiveness in several tumor types. Galectin-1 has been identified as a promising drug target using synthetic and natural inhibitors. Preclinical data suggest that galectin-1 inhibition may lead to direct antiproliferative effects in cancer cells as well as antiangiogenic effects in tumors. We provide an up-to-date overview of available data on the role of galectin-1 in different molecular and biochemical pathways involved in human malignancies. One of the major challenges faced in targeting galectin-1 is the translation of current knowledge into the design and development of effective galectin-1 inhibitors in cancer therapy. © 2013 Elsevier Ltd.


Dings R.P.M.,University of Minnesota | Miller M.C.,University of Minnesota | Nesmelova I.,University of Minnesota | Astorgues-Xerri L.,French Institute of Health and Medical Research | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2012

Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, 15N- 1H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118. © 2012 American Chemical Society.


Serova M.,AAREC Filia Research | Serova M.,French Institute of Health and Medical Research | De Gramont A.,AAREC Filia Research | Tijeras-Raballand A.,AAREC Filia Research | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib. Methods: Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1-20 μM) and second-generation drugs (0.03-20.0 μM) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells. Results: In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (≥1 μM) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, ≥1 μM rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations >0.03 μM in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets. Conclusions: Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib. © 2013 Springer-Verlag Berlin Heidelberg.


Neuzillet C.,Beaujon University Hospital | Tijeras-Raballand A.,AAREC Filia Research | De Mestier L.,Beaujon University Hospital | Cros J.,Beaujon University Hospital | And 2 more authors.
Pharmacology and Therapeutics | Year: 2014

The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant ("addicted" to the pathway) and KRAS-mutant (non-"addicted"). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it. © 2013 Elsevier Inc. All rights reserved.


Neuzillet C.,French Institute of Health and Medical Research | Tijeras-Raballand A.,AAREC Filia Research | Cohen R.,AAREC Filia Research | Cros J.,University Paris Diderot | And 3 more authors.
Pharmacology and Therapeutics | Year: 2015

The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings. © 2014 The Authors. Published by Elsevier Inc.


Cohen R.,French Institute of Health and Medical Research | Neuzillet C.,French Institute of Health and Medical Research | Neuzillet C.,Henri Mondor University Hospital | Tijeras-Raballand A.,AAREC Filia Research | And 3 more authors.
Oncotarget | Year: 2015

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.


Neuzillet C.,French Institute of Health and Medical Research | Neuzillet C.,University Paris Diderot | Tijeras-Raballand A.,AAREC Filia Research | Cros J.,University Paris Diderot | And 3 more authors.
Cancer and Metastasis Reviews | Year: 2013

Pancreatic ductal adenocarcinoma (PDAC) stands as the poorest prognostic tumor of the digestive tract, with a 5-year survival rate of less than 5 %. Therapeutic options for unresectable PDAC are extremely limited and there is a pressing need for expanded therapeutic approaches to improve current options available with gemcitabine-based regimens. With PDAC displaying one of the most prominent desmoplastic stromal reactions of all carcinomas, recent research has focused on the microenvironment surrounding PDAC cells. Secreted protein acid and rich in cysteine (SPARC), which is overexpressed in PDAC, may display tumor suppressor functions in several cancers (e.g., in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia) but also appears to be overexpressed in other tumor types (e.g., breast cancer, melanoma, and glioblastoma). The apparent contradictory functions of SPARC may yield inhibition of angiogenesis via inhibition of vascular endothelial growth factor, while promoting epithelial-to-mesenchymal transition and invasion through matrix metalloprotease expression. This feature is of particular interest in PDAC where SPARC overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and metastasis. Several therapeutic strategies to deplete stromal tissue have been developed. In this review, we focused on key preclinical and clinical data describing the role of SPARC in PDAC biology, the properties, and mechanisms of delivery of drugs that interact with SPARC and discuss the proof-of-concept clinical trials using nab-paclitaxel. © 2013 Springer Science+Business Media New York.


Neuzillet C.,French Institute of Health and Medical Research | de Gramont A.,French Institute of Health and Medical Research | de Gramont A.,AAREC Filia Research | Tijeras-Raballand A.,AAREC Filia Research | And 5 more authors.
Oncotarget | Year: 2014

Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-ß (TGF-ß) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-ß pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-ß signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-ß pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-ß as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-ß inhibition therapy.


Neuzillet C.,French Institute of Health and Medical Research | Neuzillet C.,University Paris Diderot | Hammel P.,University Paris Diderot | Tijeras-Raballand A.,AAREC Filia Research | And 2 more authors.
Cancer and Metastasis Reviews | Year: 2013

Pancreatic ductal adenocarcinoma (PAC) stands as the poorest prognostic tumor of the digestive tract with limited therapeutic options. PAC carcinogenesis is associated with the loss of function of tumor suppressor genes such as INK4A, TP53, BRCA2, and DPC4, and only a few activated oncogenes among which K-RAS mutations are the most prevalent. The K-RAS mutation occurs early in PAC carcinogenesis, driving downstream activation of MEK and ERK1/2 which promote survival, invasion, and migration of cancer cells. In PAC models, inhibition of members of the Ras-ERK pathway blocks cellular proliferation and metastasis development. As oncogenic Ras does not appear to be a suitable drug target, inhibitors targeting downstream kinases including Raf and MEK have been developed and are currently under evaluation in clinical trials. In this review, we describe the role of the Ras-ERK pathway in pancreatic carcinogenesis and as a new therapeutic target for the treatment of PAC. © 2012 Springer Science+Business Media New York.


Serova M.,AAREC Filia Research | Serova M.,French Institute of Health and Medical Research | Tijeras-Raballand A.,AAREC Filia Research | Tijeras-Raballand A.,French Institute of Health and Medical Research | And 10 more authors.
Oncotarget | Year: 2015

Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor (TβR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-β yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 μM and 10 μM galunisertib, 5 μM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-β signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.

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