Fragkos M.,CNRS Gustave Roussy Institute |
Naim V.,CNRS Gustave Roussy Institute
Cell Cycle | Year: 2017
Genomic instability is a hallmark of cancer and a common feature of human disorders, characterized by growth defects, neurodegeneration, cancer predisposition, and aging. Recent evidence has shown that DNA replication stress is a major driver of genomic instability and tumorigenesis. Cells can undergo mitosis with under-replicated DNA or unresolved DNA structures, and specific pathways are dedicated to resolving these structures during mitosis, suggesting that mitotic rescue from replication stress (MRRS) is a key process influencing genome stability and cellular homeostasis. Deregulation of MRRS following oncogene activation or loss-of-function of caretaker genes may be the cause of chromosomal aberrations that promote cancer initiation and progression. In this review, we discuss the causes and consequences of replication stress, focusing on its persistence in mitosis as well as the mechanisms and factors involved in its resolution, and the potential impact of incomplete replication or aberrant MRRS on tumorigenesis, aging and disease. © 2017 Taylor & Francis
Robert C.,CNRS Gustave Roussy Institute |
Schadendorf D.,University of Duisburg - Essen |
Messina M.,Bristol Myers Squibb |
Hodi F.S.,Dana-Farber Cancer Institute |
O'Day S.,Beverly Hills Cancer Center
Clinical Cancer Research | Year: 2013
Purpose: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to improve survival in patients with pretreated, advanced melanoma in a phase III trial. Some patients in this study who initially responded to ipilimumab treatment but later progressed were eligible for retreatment with their original randomized regimen. Here, outcomes for these patients concerning baseline characteristics, best overall response, and disease control rate are assessed and considered with respect to the overall study population. Experimental Design: In the phase III study, 676 pretreated patients were randomly allocated to treatment with ipilimumab 3 mg/kg plus gp100 vaccine, ipilimumab 3 mg/kg plus placebo, or gp100 vaccine alone. Of these patients, 32 had a partial or complete objective response or stable disease after treatment and met the eligibility criteria for retreatment, although a total of 40 patients were retreated. Results: Best overall response rates (complete responses plus partial responses) for 31 retreatmenteligible patients in the ipilimumab plus gp100 and ipilimumab plus placebo groups were 3 of 23 (13.0%) and 3 of 8 (37.5%), respectively, and disease control rates were 65.2% and 75.0%. No new types of toxicities occurred during retreatment and most events were mild-to-moderate. Conclusion: Ipilimumab provided durable objective responses and/or stable disease in qualifying patients who received retreatment upon disease progression with a similar toxicity profile to that seen during their original treatment regimen. ©2013 AACR.
Silve A.,University Paris - Sud |
Leray I.,CNRS Gustave Roussy Institute |
Mir L.M.,CNRS Gustave Roussy Institute
Bioelectrochemistry | Year: 2012
In our study, we used bleomycin to evaluate the permeabilization caused by nanosecond duration electric pulses (nanopulses). Bleomycin is a non permeant molecule which can be used both as a sensitive and quantitative marker to evaluate cell electropermeabilization. Indeed, the penetration of as few as 500 molecules is sufficient to entail a major biological effect: cell death. We show that one single nanopulse with a duration of 10. ns and a field strength of 40. kV/cm is sufficient to allow the uptake of at least 500 molecules of bleomycin in 20% of the cells when the external bleomycin concentration is 3 μM. When the external bleomycin concentration is reduced by a 100 fold, the same levels of cytotoxicity require an increase of about 25 times in the number of pulses. These results are in favor of the fact that each nanopulse creates new pores or defects on the cell membrane even if most of these pores can reseal between two consecutive pulses. Results also suggest that the cell permeability observed with classical markers when a large number of pulses are delivered results from the large number of nanopores or defects of the cell membrane created by the train of nanopulses. © 2011 Elsevier B.V.
Ruppe E.,University of Geneva |
Woerther P.-L.,CNRS Gustave Roussy Institute |
Barbier F.,La Source Hospital CHR Orleans
Annals of Intensive Care | Year: 2015
The burden of multidrug resistance in Gram-negative bacilli (GNB) now represents a daily issue for the management of antimicrobial therapy in intensive care unit (ICU) patients. In Enterobacteriaceae, the dramatic increase in the rates of resistance to third-generation cephalosporins mainly results from the spread of plasmid-borne extended-spectrum beta-lactamase (ESBL), especially those belonging to the CTX-M family. The efficacy of beta-lactam/beta-lactamase inhibitor associations for severe infections due to ESBL-producing Enterobacteriaceae has not been adequately evaluated in critically ill patients, and carbapenems still stands as the first-line choice in this situation. However, carbapenemase-producing strains have emerged worldwide over the past decade. VIM- and NDM-type metallo-beta-lactamases, OXA-48 and KPC appear as the most successful enzymes and may threaten the efficacy of carbapenems in the near future. ESBL- and carbapenemase-encoding plasmids frequently bear resistance determinants for other antimicrobial classes, including aminoglycosides (aminoglycoside-modifying enzymes or 16S rRNA methylases) and fluoroquinolones (Qnr, AAC(6′)-Ib-cr or efflux pumps), a key feature that fosters the spread of multidrug resistance in Enterobacteriaceae. In non-fermenting GNB such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, multidrug resistance may emerge following the sole occurrence of sequential chromosomal mutations, which may lead to the overproduction of intrinsic beta-lactamases, hyper-expression of efflux pumps, target modifications and permeability alterations. P. aeruginosa and A. baumannii also have the ability to acquire mobile genetic elements encoding resistance determinants, including carbapenemases. Available options for the treatment of ICU-acquired infections due to carbapenem-resistant GNB are currently scarce, and recent reports emphasizing the spread of colistin resistance in environments with high volume of polymyxins use elicit major concern. © 2015, Ruppé et al.
Dhermain F.G.,CNRS Gustave Roussy Institute |
Hau P.,University of Regensburg |
Lanfermann H.,Hannover Medical School |
Jacobs A.H.,University of Munster |
And 2 more authors.
The Lancet Neurology | Year: 2010
Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood-brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice. © 2010 Elsevier Ltd.
Souquere S.,CNRS Gustave Roussy Institute
Cell Death and Differentiation | Year: 2016
LTX-401 is an oncolytic amino acid derivative with potential immunogenic properties. Here, we demonstrate that LTX-401 selectively destroys the structure of the Golgi apparatus, as determined by means of ultrastructural analyses and fluorescence microscopic observation of cells expressing Golgi-targeted GFP reporters. Subcellular fractionation followed by mass spectrometric detection revealed that LTX-401 selectively enriched in the Golgi rather than in mitochondria or in the cytosol. The Golgi-dissociating agent Brefeldin A (BFA) reduced cell killing by LTX-401 as it partially inhibited LTX-401-induced mitochondrial release of cytochrome c and the activation of BAX. The cytotoxic effect of LTX-401 was attenuated by the double knockout of BAX and BAK, as well as the mitophagy-enforced depletion of mitochondria, yet was refractory to caspase inhibition. LTX-401 induced all major hallmarks of immunogenic cell death detectable with biosensor cell lines including calreticulin exposure, ATP release, HMGB1 exodus and a type-1 interferon response. Moreover, LTX-401-treated tumors manifested a strong lymphoid infiltration. Altogether these results support the contention that LTX-401 can stimulate immunogenic cell death through a pathway in which Golgi-localized LTX-401 operates upstream of mitochondrial membrane permeabilization.Cell Death and Differentiation advance online publication, 2 September 2016; doi:10.1038/cdd.2016.86. © 2016 Macmillan Publishers Limited, part of Springer Nature.
Postel-Vinay S.,Institute of Cancer Research |
Postel-Vinay S.,CNRS Gustave Roussy Institute |
Ashworth A.,Institute of Cancer Research
Nature Genetics | Year: 2012
A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non-small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor-resistant patients. © 2012 Nature America, Inc. All rights reserved.
Paumier A.,CNRS Gustave Roussy Institute |
Cuenca X.,CNRS Gustave Roussy Institute |
Le Pechoux C.,CNRS Gustave Roussy Institute
Cancer Treatment Reviews | Year: 2011
As multi-modality treatments are now able to ensure better local control and a lower rate of extra cranial metastases, brain relapse has become a major concern in lung cancer. As survival is poor after development of brain metastases in spite of specific treatment, prophylactic cranial irradiation (PCI) has been introduced in the 70's. PCI has been evaluated in randomized trials in both small-cell (SCLC) and non-small-cell (NSCLC) lung cancers to reduce the incidence of brain metastases and possibly increase survival. PCI reduces significantly the BM rate in both limited disease (LD) and extensive disease (ED) SCLC and in non-metastatic NSCLC. Considering SCLC, PCI significantly improves overall survival in LD (from 15% to 20% at 3. years) and ED (from 13% to 27% at 1. year) in patients who respond to first-line treatment; it should thus be part of the standard treatment in all responders in ED and in good responders in LD. No dose-effect relationship for PCI was demonstrated in LD SCLC patients so that the recommended dose is 25. Gy in 10 fractions. In NSCLC, even if the risk of brain dissemination is lower than in SCLC, it has become a challenging issue. Studies have identified subgroups at higher risk of brain failure. There are more local treatment possibilities for NSCLC patients with BM, but most of them will eventually recur so that PCI should be reconsidered. Few randomized trials have been performed and they were not able to show an effect on survival as they were underpowered. New trials are needed. © 2010 Elsevier Ltd.
Lavialle C.,CNRS Gustave Roussy Institute
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013
The development of the emerging field of 'paleovirology' allows biologists to reconstruct the evolutionary history of fossil endogenous retroviral sequences integrated within the genome of living organisms and has led to the retrieval of conserved, ancient retroviral genes 'exapted' by ancestral hosts to fulfil essential physiological roles, syncytin genes being undoubtedly among the most remarkable examples of such a phenomenon. Indeed, syncytins are 'new' genes encoding proteins derived from the envelope protein of endogenous retroviral elements that have been captured and domesticated on multiple occasions and independently in diverse mammalian species, through a process of convergent evolution. Knockout of syncytin genes in mice provided evidence for their absolute requirement for placenta development and embryo survival, via formation by cell-cell fusion of syncytial cell layers at the fetal-maternal interface. These genes of exogenous origin, acquired 'by chance' and yet still 'necessary' to carry out a basic function in placental mammals, may have been pivotal in the emergence of mammalian ancestors with a placenta from egg-laying animals via the capture of a founding retroviral env gene, subsequently replaced in the diverse mammalian lineages by new env-derived syncytin genes, each providing its host with a positive selective advantage.
Robert C.,CNRS Gustave Roussy Institute |
Arnault J.-P.,CNRS Gustave Roussy Institute |
Mateus C.,CNRS Gustave Roussy Institute
Current Opinion in Oncology | Year: 2011
Purpose of review: Targeted anticancer agents are associated with frequent skin side-effects. Several kinase inhibitors have been implicated in the appearance of borderline and malignant skin tumors such as keratoacanthomas and squamous cell carcinomas. The purpose of this review is to discuss the mechanisms as well as the management and implications of this unexpected side-effect. Recent findings: Recent findings suggest that these skin neoplasms are due to RAF inhibition and that they are more frequent and arise earlier after treatment initiation with the more specific and potent RAF inhibitors than with the multikinase and pan-RAF inhibitor sorafenib. Biological results show that RAF inhibition induces paradoxical activation of the MAPK (mitogen-activated protein kinase) signaling pathway in cells that do not carry BRAF mutation. Summary: This review discusses the various mechanisms that could be implicated in the appearance of skin tumors during the course of anti-RAF treatments as well as the implications of these findings for clinical practice and future drug development. The unexpected emergence of tumors during the course of anticancer therapies is a concern that stimulates an active field of research in the aim of understanding the underlying mechanisms and preventing if possible skin tumor initiation. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.