How to improve clinical research in a department of radiation oncology

International audienceIntroductionRadiation therapy is a core modality for cancer treatment. Around 40% of cancer cures include the use of radiotherapy, either as a single strategy or combined with other treatments. In the past decade, substantial technical advances and novel insights into radiobiological properties have considerably improved patients’ outcomes. This study overviewed the landscape of clinical research at our radiotherapy department.MethodsWe surveyed our institutional database of clinical trials to collect information for completed or ongoing radiation therapy clinical trials, from 2005 to December 2017 at the Lucien Neuwirth cancer institute.ResultsA total of 31 clinical trials were undertaken during the study period, of which 4 studies (12.9%) were industry-sponsored and 3 studies (9.7%) were launched by our radiotherapy unit. The vast majority of clinical trials (83.9%) were dedicated to unique organ localization, especially urological cancer (prostate or bladder) (42%). We also observed a shift towards more phase II trials during the study period as well as a special focus on elderly population. Over the last decade, the number of included patients increased by a 5.3 fold input, with 135 inclusions before 2011 and 720 inclusions after 2011.DiscussionThis study provided an observational and comprehensive analysis of radiotherapy research. From a monocentric point-of-view, these results reflected the on-going progress of worldwide radiotherapy research. Based on a 13-years’ experience, this study aimed at highlighting essential cues to ensure efficient and perennial researc

Mechanisms of PhotoBioModulation (PBM) focused on oral mucositis prevention and treatment: a scoping review

International audienceAbstract Background Oral mucositis (OM) is a severe complication cancer patients undergo when treated with chemoradiotherapy. Photobiomodulation (PBM) therapy also known as low-level laser therapy has been increasingly used for the treatment of such oral toxicity. The aim of this review is to discuss the mechanisms of photobiomodulation (PBM) regarding OM prevention and treatment, and more precisely to focus on the effect of PBM on tumor and healthy cells. Methods MEDLINE/PubMed, and google scholar were searched electronically. Selected studies were focusing on PBM effects on tumor and healthy cells. Results PBM interactions with the tissue and additional mechanism in OM therapy were detailed in this review. Moreover, this review highlighted a controversy about the carcinogenic effect of PBM. Indeed, Many studies reported that PBM could enhance malignant cell proliferation; suggesting that PBM would have no protective effect. In addition to acting on cancer cells, PBM may damage healthy cells. Conclusion More prospective studies are needed to assess the effect of PBM on cancer cells in order to improve its use for OM prevention and treatment

Ceramide-Enriched Membrane Domains Contribute to Targeted and Nontargeted Effects of Radiation through Modulation of PI3K/AKT Signaling in HNSCC Cells

International audienceWe investigated the potential involvement of ceramide-enriched membrane domains in radiation-induced targeted and nontargeted effects using head and neck squamous cell carcinoma with opposite radiosensitivities. In radiosensitive SCC61 cells, the proportion of targeted effects was 34% and nontargeted effects killed 32% of cells. In contrast, only targeted effects (30%) are involved in the overall death of radioresistant SQ20B cells. We then demonstrated in SCC61 cells that nontargeted cell response was driven by the formation of the radiation-induced ceramide-enriched domain. By contrast, the existence of these platforms in SQ20B cells confers a permissive region for phosphatidylinositol-3-kinase (PI3K)/AKT activation. The disruption of lipid raft results in strong inhibition of PI3K/AKT signaling, leading to radiosensitization and apparition of nontargeted effects. These results suggest that ceramide-enriched platforms play a significant role in targeted and nontargeted effects during radiotherapy and that drugs modulating cholesterol levels may be a good alternative for improving radiotherapy effectivenes

Differential Formation of Stress Granules in Radiosensitive and Radioresistant Head and Neck Squamous Cell Carcinoma Cells

International audiencePurpose: Stress granules (SGs) are cytoplasmic aggregates in which mRNAs and specific proteins are trapped in response to a variety of damaging agents. They participate in the cellular defense mechanisms. Currently, their mechanism of formation in response to ionizing radiation and their role in tumor-cell radiosensitivity remain elusive.Methods and materials: The kinetics of SG formation was investigated after the delivery of photon irradiation at different doses to head and neck squamous cell carcinoma cell lines with different radiosensitivities and the HeLa cervical cancer cell line (used as reference). In parallel, the response to a canonical inducer of SGs, sodium arsenite, was also studied. Immunolabeling of SG-specific proteins and mRNA fluorescence in situ hybridization enabled SG detection and quantification. Furthermore, a ribopuromycylation assay was used to assess the cell translational status. To determine whether reactive oxygen species were involved in SG formation, their scavenging or production was induced by pharmacologic pretreatment in both SCC61 and SQ20B cells.Results: Photon irradiation at different doses led to the formation of cytoplasmic foci that were positive for different SG markers. The presence of SGs gradually increased from 30 minutes to 2 hours postexposure in HeLa, SCC61, and Cal60 radiosensitive cells. In turn, the SQ20B and FaDu radioresistant cells did not form SGs. These results indicated a correlation between sensitivity to photon irradiation and SG formation. Moreover, SG formation was significantly reduced by reactive oxygen species scavenging using dimethyl sulfoxide in SCC61 cells, which supported their role in SG formation. However, a reciprocal experiment in SQ20B cells that depleted glutathione using buthionine sulfoximide did not restore SG formation in these cells.Conclusions: SGs are formed in response to irradiation in radiosensitive, but not in radioresistant, head and neck squamous cell carcinoma cells. Interestingly, compared with sodium arsenite-induced SGs, photon-induced SGs exhibited a different morphology and cellular localization. Moreover, photon-induced SGs were not associated with the inhibition of translation; rather, they depended on oxidative stress

Impact of hypoxia on the double-strand break repair after photon and carbon ion irradiation of radioresistant HNSCC cells

DNA double-strand breaks (DSBs) induced by photon irradiation are the most deleterious damage for cancer cells and their efficient repair may contribute to radioresistance, particularly in hypoxic conditions. Carbon ions (C-ions) act independently of the oxygen concentration and trigger complex- and clustered-DSBs difficult to repair. Understanding the interrelation between hypoxia, radiation-type, and DNA-repair is therefore essential for overcoming radioresistance. The DSBs signaling and the contribution of the canonical non-homologous end-joining (NHEJ-c) and homologous-recombination (HR) repair pathways were assessed by immunostaining in two cancer-stem-cell (CSCs) and non-CSCs HNSCC cell lines. Detection and signaling of DSBs were lower in response to C-ions than photons. Hypoxia increased the decay-rate of the detected DSBs (γH2AX) in CSCs after photons and the initiation of DSB repair signaling (P-ATM) in CSCs and non-CSCs after both radiations, but not the choice of DSB repair pathway (53BP1). Additionally, hypoxia increased the NHEJ-c (DNA-PK) and the HR pathway (RAD51) activation only after photons. Furthermore, the involvement of the HR seemed to be higher in CSCs after photons and in non-CSCs after C-ions. Taken together, our results show that C-ions may overcome the radioresistance of HNSCC associated with DNA repair, particularly in CSCs, and independently of a hypoxic microenvironment

A Review of the Role of Hypoxia in Radioresistance in Cancer Therapy

International audienceHypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solution

Impact of hypoxia on the double-strand break repair after photon and carbon ion irradiation of radioresistant HNSCC cells

International audienceDNA double-strand breaks (DSBs) induced by photon irradiation are the most deleterious damage for cancer cells and their efficient repair may contribute to radioresistance, particularly in hypoxic conditions. Carbon ions (C-ions) act independently of the oxygen concentration and trigger complex- and clustered-DSBs difficult to repair. Understanding the interrelation between hypoxia, radiation-type, and DNA-repair is therefore essential for overcoming radioresistance. The DSBs signaling and the contribution of the canonical non-homologous end-joining (NHEJ-c) and homologous-recombination (HR) repair pathways were assessed by immunostaining in two cancer-stem-cell (CSCs) and non-CSCs HNSCC cell lines. Detection and signaling of DSBs were lower in response to C-ions than photons. Hypoxia increased the decay-rate of the detected DSBs (γH2AX) in CSCs after photons and the initiation of DSB repair signaling (P-ATM) in CSCs and non-CSCs after both radiations, but not the choice of DSB repair pathway (53BP1). Additionally, hypoxia increased the NHEJ-c (DNA-PK) and the HR pathway (RAD51) activation only after photons. Furthermore, the involvement of the HR seemed to be higher in CSCs after photons and in non-CSCs after C-ions. Taken together, our results show that C-ions may overcome the radioresistance of HNSCC associated with DNA repair, particularly in CSCs, and independently of a hypoxic microenvironment

Synergic effect of cetuximab and ABT-199 combined with radiation in head and neck squamous cell carcinoma

International audiencePurpose/Objectives: Concurrent cetuximab based radio-chemotherapy is a validated scheme in head and neck cancer (HNSCC). Cancer Stem Cells (CSCs) are highly resistant to treatment, have large migratory abilities, and are hypothesized to be responsible for a significant part of recurrences. Apoptotic signaling in CSCs is a major way of treatment escape, through Bcl-2 proteins family. The aim of the present study was to evaluate the effect of cetuximab and ABT-199 combined to radiation in HNSCC CSC and non-CSC sub-populations and in tumor xenografted nude mice

Deciphering the role of stress granules in the cellular response to radiation of HNSCC cancer cells

International audienceBackground: Stress granules (SG) are cytoplasmic aggregates to which translationally stalled mRNAs are localized in response to various cellular stress, including oxidative stress, UV irradiation and chemotherapeutic agents. These cytoplasmic scaffolds are required to cope with stress. So far, little is known regarding the assembly of these structures in the context of ionizing radiation, especially whether they contribute to radioresistance/radiosensitivity of tumor cells.Aim: We conducted a comparative study in HNSCC cell lines with the aim of characterizing SG in response to photon and carbon ion irradiation