Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

<p>Abstract</p> <p>Background</p> <p>The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of <it>KRAS </it>(3%). The aim of the correlative tumour tissue studies was to investigate the relationship between <it>EGFR </it>gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX.</p> <p>Methods</p> <p>Patients included in this correlative study (<it>n </it>= 39) were a subset of patients from the clinical phase II study. The association between <it>EGFR </it>gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. <it>EGFR </it>gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene <it>CDH1 </it>was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed.</p> <p>Results</p> <p>Our study showed a significant association between increased <it>EGFR </it>gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two <it>CDH1 </it>exon 9 missense mutations (A408V and D402H) were detected.</p> <p>Conclusion</p> <p>Our finding that increased <it>EGFR </it>gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials.</p> <p>Trial registration</p> <p>Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.</p

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy

Crystalline molecular alloysDedicated to J.-M. Lehn on the occasion of his 65th birthday.

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Dialkyl-substituted monoamidinium-templated oxalate-based noncentrosymmetric 2D compounds

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Binuclear heterometallic M(iii)–Mn(ii) (M = Fe, Cr) oxalate-bridged complexes associated with a bisamidinium dication: a structural and magnetic study

International audienceTwo heterometallic oxalate-bridged dinuclear anions associated with a non-H-bond donor bisamidinium cation (Cat 2+), leading to compounds of formula Cat[Mn II (H 2 O) 4 M III (ox) 3 ] 2 Á6H 2 O (M = Fe (1) and Cr (2)), are presented. Their structural analysis reveals that the anion is the combination of a tris(oxalato)metallate(III) moiety with a tetra(aqua)manganese(II) entity. A 3D H-bonded network is formed between the crystallisation and coordination water molecules and the terminal and bridging oxalate ligands. The exchange interaction between both metal ions mediated by the oxalate bridge is À4.9 cm À1 for 1 and +1.6 cm À1 for 2 (H = ÀJS 1 S 2)

La tectonique moléculaire : des molécules à l’organisation hiérarchique de la matière complexe

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Tectonique moléculaire (conception, synthèse et étude structurale de réseaux moléculaires non-convalents)

Cette thèse présente la conception, la synthèse et l'étude structurale de réseaux moléculaires, réalisés selon les concepts de la tectonique moléculaire. Ce domaine de la chimie supramoléculaire traite de la construction d'architectures moléculaires de grande taille par l'auto-assemblage de briques actives (tectons). Afin de synthétiser ces réseaux, deux stratégies ont été utilisées.Tout d'abord, afin de réaliser des réseaux unidimensionnels stabilisés par des interactions de van der Waals, la conception et la préparation de nouveaux tectons, constitués de deux cavités (dérivés du calix[4]arène) divergentes reliées entre elles par un pont organique ou métallique, sont abordées. Ensuite, dans le but d'associer ces tectons par inclusion d'un connecteur organique, les différents essais et résultats d'inclusion sont présentés.Puis, deux familles de tectons ont été synthétisées, afin de les associer entre eux par le biais de liaisons de coordination. D'une part, nous présentons la préparation de dérivés du triphénylméthane et de leur utilisation pour la formation d'un réseau tridimensionnel, par coordination avec le cation Ag+. D'autre part, nous décrivons la synthèse de tectons bis-monodentates à base d'acide nicotinoïque ou isonicotinoïque. Enfin, nous présentons les résultats de la complexation de ces tectons avec des métaux de transition, qui a permis d'obtenir la formation d'un complexe discret (métallamacrocycle) et de réseaux uni- ou bidimensionnels.This work presents the conception, the synthesis and the structural study of molecular networks, following the concepts of molecular tectonics. The research area, based on the supramolecular chemistry, deals with the construction of infinite architectures, upon self-assembly of active bricks (tectons), through non-covalent bonds. In order to prepare such networks, two strategies have been used.In a first part, with a view to realise one-dimensional networks, stabilised by van der Waals interactions, the conception and preparation of new tectons, composed of two divergent cavities (derivatives of calix[4]arene) linked with an organic or metallic bridge, are presented. Then, with the aim of associate these tectons with an organic connector, some trials and results are presented.In a second part, we present the synthesis of two families of tectons, for the purpose of associate these organic ligands by coordination bonds. First, we present the preparation of triphenylmethane derivatives, and their use to prepare a 3-D network, by the coordination with Ag+ cation. Secondly, we describe the synthesis of new bis-monodentate tectons based on nicotinoyl or isonicotinoyl units. At the end, we present forth the results of the linking of this tectons with transition metals, who leads to the formation of a finite complex molecule (mettalamacrocycle) and one- or two-dimensional coordination networks.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

From Tectons to Composite Crystals

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Utilisation simultanée de liaisons hydrogène et de coordination en tectonique moléculaire

Based on concepts developed in the area of molecular tectonics, this work focused on the design, synthesis and structural investigations of supramolecular architectures generated under self-assembling conditions. In the first part of this work, new metallic complexes, based on mono- and di-carboxylate ligands derived from 2,2 -bipyridine or 4,7-phenanthroline, have been synthesized. A tetra components system composed of a dicationic bis-amidinium tecton, the dianionic 1,10-phenanthroline-4,7-dicarboxylate, Ag+ cation and XF6- (X= P, As, Sb) anion was shown to generate 2-D isostructural networks using a combination of CAHB and coordination-bonds. Furthermore, a tri components system composed of a dicationic bis-amidinium tecton, the dianionic 1,10-phenanthroline-4,7-dicarboxylate and Cu2+ cation has led to the formation of 3-D three-fold interpenetrated network. In the second part, the formation of hybrid networks was explored upon combining ligands 2,2 -bipyridine-6,6 -dicarboxylic acid or 4,7-phenanthroline-2,9-dicarboxylic acid with Zn(II), Cu(I/II) and Ag(I) cations in the presence or absence of an organic base. This strategy afforded an interesting 1D coordination network based on silver-silver interactions. In the third part, new bis-chelating symmetric ligands based on 2,2 -bipyridine, 2,2 -biquinoline or 1,8-naphthyridine backbones bearing polypyridyl moieties were designed and prepared. These ligands possessing both coordination sites for metal binding and recognition sites for carboxylic acid group, were used as building block for the construction of organic and hybrid networks.En utilisant les concepts de la "tectonique moléculaire", ce travail a été centré sur la conception, la synthèse ainsi que l'étude structurale d'architectures supramoléculaires hybrides, organiques/inorganiques, obtenues dans des conditions d'auto-assemblage. Dans la première partie, des nouveaux complexes métalliques, obtenus à partir de ligands mono- et di-carboxylate dérivés de 2,2 -bipyridine ou de 4,7-phenanthroline, ont été synthétisés. Des architectures bidimensionnelles isostructurales à quatre composants ont été obtenues en combinant un tecton dianionique 1,10-phenanthroline-4,7-dicarboxylate, un dication de type bisamidinium, le cation Ag+ ainsi que des anions XF6- (X= P, As, Sb). De plus, une architecture tridimensionnelle triplement interpénétrée a été formée à partir de 1,10-phenanthroline-4,7-dicarboxylate, dication bisamidinium et le cation Cu2+. Dans la deuxième partie, la coordination des cations métalliques Zn(II), Cu(I/II) and Ag(I) par les ligands 2,2 -bipyridine-6,6 - acide dicarboxylique ou 4,7-phenanthroline-2,9-acide dicarboxylique ainsi que la formation de réseaux moléculaires ont été étudiées. Cette investigation a conduit à la formation d'un réseau de coordination monodimensionnel basé sur des interactions Ag-Ag. Enfin, dans la dernière partie, nous nous sommes intéressés à une nouvelle famille de ligands basés sur des squelettes de type 2,2 -bipyridine, 2,2 -biquinoline ou 1,8-naphthyridine portant des groupes pyridyls. Ces ligands portent de sites de coordination pour les métaux et un motif de reconnaissance pour le groupe carboxylique, particulièrement utile pour la formation de réseaux hybrides.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF