Réparation, Radiations et Thérapies innovantes anticancer

Publications de l’équipe

Année de publication : 2016

Pierre-Marie Girard, Atousa Arbabian, Michel Fleury, Gérard Bauville, Vincent Puech, Marie Dutreix, João Santos Sousa (2016 Jul 2)

Synergistic Effect of H2O2 and NO2 in Cell Death Induced by Cold Atmospheric He Plasma.

Scientific reports : 29098 : DOI : 10.1038/srep29098 En savoir plus
Résumé

Cold atmospheric pressure plasmas (CAPPs) have emerged over the last decade as a new promising therapy to fight cancer. CAPPs’ antitumor activity is primarily due to the delivery of reactive oxygen and nitrogen species (RONS), but the precise determination of the constituents linked to this anticancer process remains to be done. In the present study, using a micro-plasma jet produced in helium (He), we demonstrate that the concentration of H2O2, NO2(-) and NO3(-) can fully account for the majority of RONS produced in plasma-activated buffer. The role of these species on the viability of normal and tumour cell lines was investigated. Although the degree of sensitivity to H2O2 is cell-type dependent, we show that H2O2 alone cannot account for the toxicity of He plasma. Indeed, NO2(-), but not NO3(-), acts in synergy with H2O2 to enhance cell death in normal and tumour cell lines to a level similar to that observed after plasma treatment. Our findings suggest that the efficiency of plasma treatment strongly depends on the combination of H2O2 and NO2(-) in determined concentrations. We also show that the interaction of the He plasma jet with the ambient air is required to generate NO2(-) and NO3(-) in solution.

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G Laurent, C Bernhard, S Dufort, G Jiménez Sánchez, R Bazzi, F Boschetti, M Moreau, T H Vu, B Collin, A Oudot, N Herath, H Requardt, S Laurent, L Vander Elst, R Muller, M Dutreix, M Meyer, F Brunotte, P Perriat, F Lux, O Tillement, G Le Duc, F Denat, S Roux (2016 Jun 1)

Minor changes in the macrocyclic ligands but major consequences on the efficiency of gold nanoparticles designed for radiosensitization.

Nanoscale : 12054-65 : DOI : 10.1039/c6nr01228k En savoir plus
Résumé

Many studies have been devoted to adapting the design of gold nanoparticles to efficiently exploit their promising capability to enhance the effects of radiotherapy. In particular, the addition of magnetic resonance imaging modality constitutes an attractive strategy for enhancing the selectivity of radiotherapy since it allows the determination of the most suited delay between the injection of nanoparticles and irradiation. This requires the functionalization of the gold core by an organic shell composed of thiolated gadolinium chelates. The risk of nephrogenic systemic fibrosis induced by the release of gadolinium ions should encourage the use of macrocyclic chelators which form highly stable and inert complexes with gadolinium ions. In this context, three types of gold nanoparticles (Au@DTDOTA, Au@TADOTA and Au@TADOTAGA) combining MRI, nuclear imaging and radiosensitization have been developed with different macrocyclic ligands anchored onto the gold cores. Despite similarities in size and organic shell composition, the distribution of gadolinium chelate-coated gold nanoparticles (Au@TADOTA-Gd and Au@TADOTAGA-Gd) in the tumor zone is clearly different. As a result, the intravenous injection of Au@TADOTAGA-Gd prior to the irradiation of 9L gliosarcoma bearing rats leads to the highest increase in lifespan whereas the radiophysical effects of Au@TADOTAGA-Gd and Au@TADOTA-Gd are very similar.

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C Le Tourneau, B Dreno, Y Kirova, J J Grob, T Jouary, C Dutriaux, L Thomas, C Lebbé, L Mortier, P Saiag, M F Avril, E Maubec, P Joly, P Bey, J M Cosset, J S Sun, B Asselain, F Devun, M E Marty, M Dutreix (2016 May 4)

First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

British journal of cancer : 1199-205 : DOI : 10.1038/bjc.2016.120 En savoir plus
Résumé

DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma.

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Tina Gruosso, Virginie Mieulet, Melissa Cardon, Brigitte Bourachot, Yann Kieffer, Flavien Devun, Thierry Dubois, Marie Dutreix, Anne Vincent-Salomon, Kyle Malcolm Miller, Fatima Mechta-Grigoriou (2016 Mar 24)

Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients.

EMBO molecular medicine : 527-49 : DOI : 10.15252/emmm.201505891 En savoir plus
Résumé

Anti-cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD-/Nrf2-antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly-ubiquitination and promotes its degradation by the proteasome. ROS-mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple-Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2-antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS-mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.

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Julian Biau, Flavien Devun, Pierre Verrelle, Marie Dutreix (2016 Feb 27)

[Dbait: An innovative concept to inhibit DNA repair and treat cancer].

Bulletin du cancer : 227-35 : DOI : 10.1016/j.bulcan.2016.01.007 En savoir plus
Résumé

The ability of cancer cells to recognize damage and initiate DNA repair is an important mechanism for therapeutic resistance. The use of inhibitors of DNA damage repair or signaling pathways appears to provide a unique opportunity for targeting genetic differences between tumor and normal cells. In this review, we firstly describe the main DNA lesions induced by the different treatments and the pathways involved in their repair. Then we review the mechanism of action and applications of an innovative DNA repair inhibitor: Dbait (and its clinical form DT01). Dbait/DT01 consists of 32bp deoxyribonucleotides forming an intramolecular DNA double helix that mimics DNA lesions. They act as a bait for DNA damage signaling enzymes, the polyadenyl-ribose polymerase (PARP), and the DNA-dependent kinase (DNA-PK), inducing a « false » DNA damage signal and ultimately inhibiting recruitment at the damage site of many proteins involved in double-strand break and single-strand break repair pathways. Preclinical studies have demonstrated the capacity of Dbait/DT01 to improve the efficiency of (i) chemotherapy in colorectal cancer or hepatocellular carcinoma models, (ii) radiofrequency ablative in colorectal cancer liver metastases models, and (iii) radiotherapy in xenografted mice with head & neck squamous cell carcinoma, glioblastoma and melanoma. Following this good preclinical results, we performed a first-in-human phase 1-2a study evaluating the safety and efficacy of the combination of DT01 with radiotherapy for the treatment of skin metastases of melanoma. Twenty-three patients were included. No dose-limiting toxicity was observed. An objective response was observed in 59% lesions, including 30% complete responses. This first promising clinical efficacy provides future potential interesting clinical development of Dbait/DT01 with various anticancer treatments.

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Claire Viallard, Jean-Michel Chezal, Florence Mishellany, Isabelle Ranchon-Cole, Bruno Pereira, Aurélie Herbette, Sophie Besse, Zied Boudhraa, Nathalie Jacquemot, Anne Cayre, Elisabeth Miot-Noirault, Jian-Sheng Sun, Marie Dutreix, Françoise Degoul (2016 Feb 18)

Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy.

Oncotarget : 12927-36 : DOI : 10.18632/oncotarget.7340 En savoir plus
Résumé

Radiolabelled melanin ligands offer an interesting strategy for the treatment of disseminated pigmented melanoma. One of these molecules, ICF01012 labelled with iodine 131, induced a significant slowing of melanoma growth. Here, we have explored the combination of [131I]ICF01012 with coDbait, a DNA repair inhibitor, to overcome melanoma radioresistance and increase targeted radionuclide therapy (TRT) efficacy. In human SK-Mel 3 melanoma xenograft, the addition of coDbait had a synergistic effect on tumor growth and median survival. The anti-tumor effect was additive in murine syngeneic B16Bl6 model whereas coDbait combination with [131I]ICF01012 did not increase TRT side effects in secondary pigmented tissues (e.g. hair follicles, eyes). Our results confirm that DNA lesions induced by TRT were not enhanced with coDbait association but, the presence of micronuclei and cell cycle blockade in tumor shows that coDbait acts by interrupting or delaying DNA repair. In this study, we demonstrate for the first time, the usefulness of DNA repair traps in the context of targeted radionuclide therapy.

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Tinatin Kakchekeeva, Cedric Demtröder, Nirmitha I Herath, Dominic Griffiths, Jared Torkington, Wiebke Solaß, Marie Dutreix, Marc A Reymond (2016 Feb 5)

In Vivo Feasibility of Electrostatic Precipitation as an Adjunct to Pressurized Intraperitoneal Aerosol Chemotherapy (ePIPAC).

Annals of surgical oncology En savoir plus
Résumé

Intraperitoneal chemotherapy is limited by tissue penetration. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve drug uptake by utilizing the physical properties of gas and pressure. This study investigated the effect of adding electrostatic precipitation to further enhance the pharmacologic properties of this technique.

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Année de publication : 2015

Nirmitha I Herath, Flavien Devun, Marie-Christine Lienafa, Aurélie Herbette, Alban Denys, Jian-Sheng Sun, Marie Dutreix (2015 Dec 6)

The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis.

Molecular cancer therapeutics : 15-22 : DOI : 10.1158/1535-7163.MCT-15-0408 En savoir plus
Résumé

Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm(2), P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer.

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Nadja Khalili-Harbi, Nirmitha Herath, Wiebke Solass, Urs Giger-Pabst, Marie Dutreix, Marc Andre Reymond (2015 Oct 14)

Pressurized intraluminal aerosol chemotherapy with Dbait in the distal esophagus of swine.

Endoscopy : 184-7 : DOI : 10.1055/s-0034-1393180 En savoir plus
Résumé

A novel therapeutic concept, pressurized intraluminal aerosol chemotherapy (PILAC), and a corresponding device for distributing drugs to the mucosa and submucosa of the distal esophagus are presented.

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D Corcos (2015 Aug 20)

Food-Nonfood Discrimination in Ancestral Vertebrates: Gamete Cannibalism and the Origin of the Adaptive Immune System.

Scandinavian journal of immunology : 409-17 : DOI : 10.1111/sji.12348 En savoir plus
Résumé

Adaptive immunity is a complex system that appeared twice in vertebrates (in gnathostomes and in jawless fish) although it is not required for invertebrate defence. The adaptive immune system is tightly associated with self-non-self discrimination, and it is now clear that this interplay is not limited to the prevention of autoreactivity. Micro-organisms are usually considered for their pathogenicity or symbiotic ability, but, for most small metazoans, they mainly constitute food. Vertebrates are characterized by feeding by predation on larger preys, when compared to their ancestors who were filter feeders and ate micro-organisms. Predation gives a strong selective advantage, not only due to the availability of new food resources but also by the ability to eliminate competitors for environmental resources (intraguild predation (IGP)). Unlike size-structured IGP, intraspecific predation of juveniles, zygotes or gametes can be detrimental for species fitness in some circumstances. The ability of individuals to recognize highly polymorphic molecules on the surface of gametes present in the plankton and so distinguish self versus non-self gametes might have constituted a strong selective advantage in intraspecific competition. Here, I propose the theory that the capacity to rearrange receptors has been selected in ancestral vertebrates as a consequence of this strong need for discriminating between hetero-cannibalism versus filial cannibalism. This evolutionary origin sheds light on presently unexplained features of the immune system, including the existence of regulatory T cells and of non-pathogenic natural autoimmunity.

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V Favaudon, C Fouillade, M-C Vozenin (2015 Aug 17)

[Ultrahigh dose-rate, « flash » irradiation minimizes the side-effects of radiotherapy].

Cancer radiothérapie : journal de la Société française de radiothérapie oncologique : 526-31 : DOI : 10.1016/j.canrad.2015.04.006 En savoir plus
Résumé

Pencil beam scanning and filter free techniques may involve dose-rates considerably higher than those used in conventional external-beam radiotherapy. Our purpose was to investigate normal tissue and tumour responses in vivo to short pulses of radiation.

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I Kuperstein, E Bonnet, H-A Nguyen, D Cohen, E Viara, L Grieco, S Fourquet, L Calzone, C Russo, M Kondratova, M Dutreix, E Barillot, A Zinovyev (2015 Jul 21)

Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps.

Oncogenesis : e160 : DOI : 10.1038/oncsis.2015.19 En savoir plus
Résumé

Cancerogenesis is driven by mutations leading to aberrant functioning of a complex network of molecular interactions and simultaneously affecting multiple cellular functions. Therefore, the successful application of bioinformatics and systems biology methods for analysis of high-throughput data in cancer research heavily depends on availability of global and detailed reconstructions of signalling networks amenable for computational analysis. We present here the Atlas of Cancer Signalling Network (ACSN), an interactive and comprehensive map of molecular mechanisms implicated in cancer. The resource includes tools for map navigation, visualization and analysis of molecular data in the context of signalling network maps. Constructing and updating ACSN involves careful manual curation of molecular biology literature and participation of experts in the corresponding fields. The cancer-oriented content of ACSN is completely original and covers major mechanisms involved in cancer progression, including DNA repair, cell survival, apoptosis, cell cycle, EMT and cell motility. Cell signalling mechanisms are depicted in detail, together creating a seamless ‘geographic-like’ map of molecular interactions frequently deregulated in cancer. The map is browsable using NaviCell web interface using the Google Maps engine and semantic zooming principle. The associated web-blog provides a forum for commenting and curating the ACSN content. ACSN allows uploading heterogeneous omics data from users on top of the maps for visualization and performing functional analyses. We suggest several scenarios for ACSN application in cancer research, particularly for visualizing high-throughput data, starting from small interfering RNA-based screening results or mutation frequencies to innovative ways of exploring transcriptomes and phosphoproteomes. Integration and analysis of these data in the context of ACSN may help interpret their biological significance and formulate mechanistic hypotheses. ACSN may also support patient stratification, prediction of treatment response and resistance to cancer drugs, as well as design of novel treatment strategies.

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Ewa Kotula, Nathalie Berthault, Celine Agrario, Marie-Christine Lienafa, Anthony Simon, Florent Dingli, Damarys Loew, Vonick Sibut, Simon Saule, Marie Dutreix (2015 May 29)

DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion.

Cell cycle (Georgetown, Tex.) : 1961-72 : DOI : 10.1080/15384101.2015.1026522 En savoir plus
Résumé

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair and is also frequently overexpressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. We found that DNA-PKcs participates in melanoma primary tumor and metastasis development by stimulating angiogenesis, migration and invasion. Comparison of conditioned medium content from DNA-PKcs-proficient and deficient cells reveals that DNA-PKcs controls secretion of at least 103 proteins (including 44 metastasis-associated with FBLN1, SERPINA3, MMP-8, HSPG2 and the inhibitors of matrix metalloproteinases, such as α-2M and TIMP-2). High throughput analysis of secretomes, proteomes and transcriptomes, indicate that DNA-PKcs regulates the secretion of 85 proteins without affecting their gene expression. Our data demonstrate that DNA-PKcs has a pro-metastatic activity via the modification of the tumor microenvironment. This study shows for the first time a direct link between DNA damage repair and cancer metastasis and highlights the importance of DNA-PKcs as a potential target for anti-metastatic treatment.

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Vincent Favaudon, Charles Fouillade, Marie-Catherine Vozenin (2015 Mar 7)

[The radiotherapy FLASH to save healthy tissues].

Médecine sciences : M/S : 121-3 : DOI : 10.1051/medsci/20153102002 En savoir plus
Résumé

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Année de publication : 2014

Julian Biau, Flavien Devun, Wael Jdey, Ewa Kotula, Maria Quanz, Emmanuel Chautard, Mano Sayarath, Jian-Sheng Sun, Pierre Verrelle, Marie Dutreix (2014 Oct 23)

A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.

Neoplasia (New York, N.Y.) : 835-44 : DOI : 10.1016/j.neo.2014.08.008 En savoir plus
Résumé

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of « palliative » RT (10 × 3 Gy) or « radical » RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the « palliative » protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the « radical » protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).

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