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 ..

Gadolinium-Based Nanoparticles as a powerful radiosensitizing strategy in head and neck carcinoma stem- and non-stem cells

National audienc

Gadolinium-based nanoparticles sensitize head and neck carcinoma stem and nonstem cells to low and high LET radiation

International audienceHead and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. Several strategies aiming at radiosensitizing these tumors are currently being developed, one of these relying on the use of nanoparticles including high Z elements such as gadolinium (Z=64). Once delivered to the tumor, gadolinium-based nanoparticles (GBNs) should amplify the efficacy of radiotherapy through the generation of electron Auger cascades and secondary electrons. This study aims at demonstrating the in vitro and in vivo radiosensitizing effect of sub-5 nm GBNs (composed of a core of gadolinium oxide, a shell of polysiloxane, and functionalized by diethylene triaminepentaacetic acid) in a SQ20B radioresistant HNSCC model. Owing to the crucial role of cancer stem cells in tumor initiation, disease recurrence and radioresistance, the radiosensitizing effect of GBNs was also tested in SQ20B stem-like cells. The association of 0,6 mM GBNs with a photon or a 33.6 keV/µm carbon ion irradiation decrease significantly SQ20B cell survival. Radiosensitization goes through the increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, the inhibition of cell proliferation, each contributing to the commitment into apoptosis. The combined treatment of GBNs with irradiation can also overcome the resistance of SQ20B stem-like cells. Using an SQ20B tumor-bearing mouse model, we also demonstrate that GBNs in conjunction with photon irradiation significantly retard tumor growth compared with the radiation alone, with complete remission in some mice. Significantly, an increase in apoptosis and decrease in cell proliferation are also detected inside tumors in the combined treatment group. These results suggest the interesting potential of GBNs in sensitizing resistant HNSCC tumors to radiotherapy and their possible contribution towards overcoming limitations of current cancer treatment. This project was conducted under the framework of LANTHARAD (PDC019 CLARA 2010), PRRH-ETOILE and LABEX PRIMES (2012

Challenges of combining gadolinium-based nanoparticles with low- and high-LET radiation IN THE treatment of head and neck squamous cell carcinoma

Communication oraleInternational audienc

Gadolinium based nanoparticles for radiosensitization of head and neck squamous cell carcinoma

International audiencePurpose: Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy that displays intrinsic resistance to radio- and chemotherapy. The aim of this study is to radiosensitize these tumors using gadolinium based nanoparticles (GBN) made of a polysiloxane matrix and surrounded by gadolinium chelates. The nanoparticles in the tumors should enhance the efficacy of radiotherapy (thanks to the high Z of gadolinium) through the generation of electron Auger cascade and secondary electrons

Challenges of combining gadolinium-based nanoparticles with low- and high-LET radiation IN THE treatment of head and neck squamous cell carcinoma

Communication oraleInternational audienc

Gadolinium based nanoparticles as radiosensitizing agents for radioresistant head and neck tumours

International audienceRadiotherapy is one of the main therapies for cancer, but it remains limited when tumours are radioresistant such glioblastoma, head and neck tumours, osteo and chondrosarcomas for example. Several strategies aiming at radiosensitizing these resistant tumours are under development. One of those relies on the use of high density nanoparticles, which once delivered into the tumour should deliver secondary radiations amplifying the radiotherapy efficiency. A previous reported study from our consortium showed that Gadolinium Based Nanoparticles (GBN) were able to induce a clonogenic death of SQ20B cells in culture (human head and neck carcinoma cells). The present study aimed at the demonstration of the in-vivo radiosensitizing effect of these GBN on SQ20B xenograft tumour. Radiation Therapy (RT) was performed using a biological X-Ray Irradiator (X-RAD 320) (Byfleet, Surrey) with 320 KV X-rays. The field of irradiation was adapted according to tumor volume by using an adjustable collimator positioned 35 cm from the animals. The dose rate was of 2 Gy.min-1. Four/five weeks after tumor grafting, mice with tumor volume less than 400 mm3 were randomly selected for radiotherapy 5 minutes after intratumoral (IT) injection of either GBN or saline. Four groups of rats were compared: IT injection of saline only (Control) (n = 9), GBN IT injection only (GBN injection) (n = 9), IT injection of saline + 10 Gy radiation (IR 10Gy) (n = 13), and IT injection of GBN + 10 Gy (IR 10Gy + GBN) (n = 10). Compared to the progressive and massive increase in tumor volume observed in the control groups (control and GBN injection groups), 10 Gy radiation stabilized tumor evolution between the second and the third week after radiation. The tumors then started to develop again with a growth curve similar to that of the control group. In contrast, the combination of GBN with 10 Gy radiation limited spectacularly the SQ20B tumors growth. At the end of week 6, the mean reduction in tumor volume in the IR 10Gy + GBN group, was of 626 and 388% (P = 0,003) compared, respectively, to the control and only irradiated tumors. Moreover, in the end of our therapy study, tumors have disappeared in two mice given 10 Gy with GBN treatment. Combined with the in-vitro study, the reported results demonstrate a major radiosensitizing effect of Gadolinium Based Nanoparticles on radioresistant tumours such as Head and Neck carcinomas

In Vitro Radiosensitizing Effects of Ultrasmall Gadolinium Based Particles on Tumour Cells

International audienc

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 ..