2012 Activity Report of the Regional Research Programme on Hadrontherapy for the ETOILE Center

2012 is the penultimate year of financial support by the CPER 2007-2013 for ETOILE's research program, sustained by the PRRH at the University Claude Bernard. As with each edition we make the annual review of the research in this group, so active for over 12 years now. Over the difficulties in the decision-making process for the implementation of the ETOILE Center, towards which all our efforts are focussed, some "themes" (work packages) were strengthened, others have progressed, or have been dropped. This is the case of the eighth theme (technological developments), centered around the technology for rotative beam distribution heads (gantries) and, after being synchronized with the developments of ULICE's WP6, remained so by ceasing its activities, coinciding also with the retirement of its historic leader at IPNL, Marcel Bajard. Topic number 5 ("In silico simulations") has suffered the departure of its leader, Benjamin Ribba, although the work has still been provided by Branka Bernard, a former postdoctoral fellow in Lyon Sud, and now back home in Croatia, still in contract with UCBL for the ULICE project. Aside from these two issues (and the fact that the theme "Medico-economical simulations" is now directly linked to the first one ("Medical Project"), the rest of the teams are growing, as evidenced by the publication statistics at the beginning of this report. This is obviously due to the financial support of our always faithful regional institutions, but also to the synergy that the previous years, the European projects, the arrival of the PRIMES LabEx, and the national France Hadron infrastructure have managed to impulse. The Rhone-Alpes hadron team, which naturally includes the researchers of LPC at Clermont, should also see its influence result in a strong presence in France Hadron's regional node, which is being organized. The future of this regional research is not yet fully guaranteed, especially in the still uncertain context of ETOILE, but the tracks are beginning to emerge to allow past and present efforts translate into a long future that we all want to see established. Each of the researchers in PRRH is aware that 2013 will be (and already is) the year of great challenge : for ETOILE, for the PRRH, for hadron therapy in France, for French hadrontherapy in Europe (after the opening and beginning of treatments in the German [HIT Heidelberg, Marburg], Italian [CNAO, Pavia] and Austrian [MedAustron, Wien Neuerstadt]) centers. Let us meet again in early 2014 for a comprehensive review of the past and a perspective for the future ..

Ab Initio Screening Approach for the Discovery of Lignin Polymer Breaking Pathways

The directed depolymerization of lignin biopolymers is of utmost relevance for the valorization or commercialization of biomass fuels. We present a computational and theoretical screening approach to identify potential cleavage pathways and resulting fragments that are formed during depolymerization of lignin oligomers containing two to six monomers. We have developed a chemical discovery technique to identify the chemically relevant putative fragments in eight known polymeric linkage types of lignin. Obtaining these structures is a crucial precursor to the development of any further kinetic modeling. We have developed this approach by adapting steered molecular dynamics calculations under constant force and varying the points of applied force in the molecule to diversify the screening approach. Key observations include relationships between abundance and breaking frequency, the relative diversity of potential pathways for a given linkage, and the observation that readily cleaved bonds can destabilize adjacent bonds, causing subsequent automatic cleavage.Massachusetts Institute of Technology (Research Support Corporation, Reed Grant)United States. Dept. of Energy. Computational Science Graduate Fellowship Program (DOE-CSGF)Burroughs Wellcome Fund (Career Award at the Scientific Interface

ABT-737, A BH3 MIMETIC, LEADS TO RADIOSENSITIZATION OF HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA INDUCTION OF INTRAMITOCHONDRIAL OXIDATIVE STRESS

International audienceHead and neck squamous cell carcinomas (HNSCC), the sixth most common cancer worldwide, have an overall 5-year survival rate around 30% and this despite new therapeutic approaches including surgery, chemo-radiotherapy or targeted-therapies. Moreover, the classical therapy combining platinum-based chemotherapy and radiotherapy is associated with acute and chronic toxicities and a severely reduced quality of life. In order to significantly improve overall patient survival and reduce treatment toxicity, new drugs or combined treatments are urgently needed. The resistance of HNSCC cells to chemoradiotherapy is partly due to the over-expression of anti-apoptotic members of the Bcl-2 protein family, resulting in an inhibition of apoptosis in these cancer cells. In this context, Bcl-2 inhibition strategies have recently re-emerged as promising tools to specifically target these resistant cancer cells. ABT-737, a BH3-mimetic family member, binds and inhibits anti-apoptotic Bcl-xL, Bcl-2, and Bcl-w proteins but shows little affinity for Mcl-1 and Bcl2A1 (Osterdorf et al., 2005). Beside their role in the induction of the mitochondrial transition pore through the release of pro-apoptotic proteins Bax and Bak, Bcl-2 targeting strategies have been reported to act on the redox properties of Bcl-2 proteins. Thus Wilkins et al. (2012) recently demonstrated that Bcl-2 activates the 2-oxoglutarate carrier (OGC), the main carrier of glutathione (GSH) into mitochondria. GSH, the main nonenzymatic antioxidant, has to be imported from the cytosol in order to regulate the intramitochondrial redox balance. Our work demonstrates that a pre-treatment with ABT737 before irradiation can radio-sensitize HNSCC cell lines of graduate radiosensitivities and triggers apoptotic cell death. We show that the combined therapy triggers cell death through the generation of a major intra-mitochondrial oxidative stress. References: Oltersdorf et al. Nature (2005) 435:677 Wilkins et al. Free Radic Biol Med (2012) 52:410 This project was conducted under the framework of PRRH-ETOILE and LABEX PRIMES (ANR-11LABX-0063)

Un inhibiteur de Bcl-2, l'ABT-737, augmente la réponse à l'irradiation des carcinomes épidermoïdes des voies aéro-digestives supérieures en ciblant le glutathion intra-mitochondrial

Communication oraleNational audienc

Preferential targeting of cancer stem cells in the radiosensitizing effect of ABT-737 on Head and Neck Squamous Cell Carcinoma

International audienceIntrinsic radioresistance of cancer cells remains a fundamental barrier to obtain the maximal efficacy of radiotherapy (RT) for the treatment of HNSCC. This resistance to RT is due, in large part, to aberrant inhibition of apoptosis through overexpression and/or hyperactivation of signaling proteins and pathways. Among these, some members of the Blc-2 protein family, such as Bcl-2 and Bcl-XL, contribute this resistance by inhibiting the intrinsic mitochondrial pathway. ABT-737 is a rationally designed small molecule that binds with high affinity to Bcl-2 and Bcl-XL and antagonizes their anti-apoptotic function, thereby inducing apoptosis in many cancer cell types. Although ABT-737 has been shown to make HNSCC cells more susceptible to conventional chemotherapy, no prior study investigating the effect of ABT-737 in combination with RT has been undertaken for the treatment of HNSCC.We investigated the effect of ABT-737 combined to radiation on 4 HNSCC cell lines of graduate sensitivity. All of them strongly express BcL-Xl and Bcl-2 at a lesser extent, two primary targets of ABT-737, and a good correlation was obtained between the pro-apoptotic protein Bak expression and the survival fraction at 2Gy of the cell lines. Although ABT-737 is modestly effective as a monotherapy against HNSCC, isobolographic analysis demonstrated that it potently synergizes with RT to kill tumor cells through the intrinsic apoptotic pathway. We also investigated the potential of this therapeutic association on cancer stem cells (CSCs) obtained from the SQ20B cell line. A strong radiosensitizing effect was obtained with ABT-737 alone but combination with RT resulted in a very efficient CSC killing. Finally, the combination of ABT-737 to RT resulted in a significant tumor growth delay in a mouse xenograft model.Altogether, these data demonstrate potent synergy between ABT-737 and RT in the killing of HNSCC cells and reveal a promising therapeutic benefit including inhibition of tumor relapse.Supported by ANR-11-LABX-0063, Lyric Grant INCa-DGOS-4664 and CPER ETOILE

An experimental and analytical study of the elasticity of model polyurethane networks crosslinked by tri- and quadriisocyanate

The original publication is available at www.springerlink.com : http://link.springer.com/article/10.1007%2Fs00396-009-2145-6?LI=truePolyurethane networks have been prepared from a mix of tri- and quadriisocyanate and from two types of diols, polyether-based (with molar masses of 1,000, 2,000, and 4,000 g/mol) and polyester-based (1,035 g/mol). The weight fraction of sol has been measured, as well as the elastic shear modulus of the gels. It has been found that the statistical theory of network formation predicts a weight fraction of sol in agreement with the experimental results, but its standard combination with the theory of rubber elasticity disagrees significantly with the elastic modulus measured. This suggests a discrepancy between theory and experiment in terms of elastically active chains. In contrast, the assumption that all nodes in the gel, or even in the system, are elastically active gives much better predictions for the system considered.ANR JCJC MELA

Experimental study and numerical simulation of the vertical bounce of a polymer ball over a wide temperature range

The dependence to temperature of the rebound of a solid polymer ball on a rigid slab is investigated. An acrylate polymer ball is brought to a wide range of temperatures, covering its glass to rubbery transition, and let fall on a granite slab while the coe cient of restitution, duration of contact, and force history are measured experimentally. The ball fabrication is controlled in the lab, allowing the mechanical characterization of the material by classic dynamic mechanical analysis (DMA). Finite element simulations of the rebound at various temperatures are run, consider- ing the material as viscoelatic and as satisfying a WLF equation for its time-temperature superposition property. A comparison between the experiments and the simulations shows the strong link between viscoelasticity and time-temperature superposition properties of the material and the bounce characteristics of the ball