@article{cancers13215402,

title = {Voluntary Wheel Running Does Not Enhance Radiotherapy Efficiency in a Preclinical Model of Prostate Cancer: The Importance of Physical Activity Modalities?},

author = {Suzanne Dufresne and Cindy Richard and Arthur Dieumegard and Luz Orfila and Gregory Delpon and Sophie Chiavassa and Brice Martin and Laurent Rouvière and Jean-Michel Escoffre and Edward Oujagir and Baudouin Denis de Senneville and Ayache Bouakaz and Nathalie Rioux-Leclercq and Vincent Potiron and Amélie Rébillard},

url = {https://www.mdpi.com/2072-6694/13/21/5402},

doi = {10.3390/cancers13215402},

issn = {2072-6694},

year  = {2021},

date = {2021-10-28},

urldate = {2021-01-01},

journal = {Cancers},

volume = {13},

number = {21},

abstract = {Physical activity is increasingly recognized as a strategy able to improve cancer patient outcome, and its potential to enhance treatment response is promising, despite being unclear. In our study we used a preclinical model of prostate cancer to investigate whether voluntary wheel running (VWR) could improve tumor perfusion and enhance radiotherapy (RT) efficiency. Nude athymic mice were injected with PC-3 cancer cells and either remained inactive or were housed with running wheels. Apparent microbubble transport was enhanced with VWR, which we hypothesized could improve the RT response. When repeating the experiments and adding RT, however, we observed that VWR did not influence RT efficiency. These findings contrasted with previous results and prompted us to evaluate if the lack of effects observed on tumor growth could be attributable to the physical activity modality used. Using PC-3 and PPC-1 xenografts, we randomized mice to either inactive controls, VWR, or treadmill running (TR). In both models, TR (but not VWR) slowed down tumor growth, suggesting that the anti-cancer effects of physical activity are dependent on its modalities. Providing a better understanding of which activity type should be recommended to cancer patients thus appears essential to improve treatment outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34391648,

title = {[Combination radiotherapy-immunotherapy in genitourinary cancer]},

author = {L Ollivier and V Guimas and E Rio and L Vaugier and I Masson and V Libois and M Labbé and D Fradin and V Potiron and S Supiot},

doi = {10.1016/j.canrad.2021.06.033},

issn = {1769-6658},

year  = {2021},

date = {2021-10-21},

urldate = {2021-10-01},

journal = {Cancer Radiother},

volume = {25},

number = {6-7},

pages = {565--569},

abstract = {Immunotherapy occupies a growing place in urologic oncology, mainly for kidney and bladder cancers. On the basis of encouraging preclinical work, the combination of immunotherapy with radiotherapy aims to increase the tumor response, including in metastatic tumors, which raises many hopes, which this article reviews.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33920758,

title = {A Monte Carlo Determination of Dose and Range Uncertainties for Preclinical Studies with a Proton Beam},

author = {Arthur Bongrand and Charbel Koumeir and Daphnée Villoing and Arnaud Guertin and Ferid Haddad and Vincent Métivier and Freddy Poirier and Vincent Potiron and Noël Servagent and Stéphane Supiot and Grégory Delpon and Sophie Chiavassa},

doi = {10.3390/cancers13081889},

issn = {2072-6694},

year  = {2021},

date = {2021-04-15},

urldate = {2021-04-01},

journal = {Cancers (Basel)},

volume = {13},

number = {8},

abstract = {Proton therapy (PRT) is an irradiation technique that aims at limiting normal tissue damage while maintaining the tumor response. To study its specificities, the ARRONAX cyclotron is currently developing a preclinical structure compatible with biological experiments. A prerequisite is to identify and control uncertainties on the ARRONAX beamline, which can lead to significant biases in the observed biological results and dose-response relationships, as for any facility. This paper summarizes and quantifies the impact of uncertainty on proton range, absorbed dose, and dose homogeneity in a preclinical context of cell or small animal irradiation on the Bragg curve, using Monte Carlo simulations. All possible sources of uncertainty were investigated and discussed independently. Those with a significant impact were identified, and protocols were established to reduce their consequences. Overall, the uncertainties evaluated were similar to those from clinical practice and are considered compatible with the performance of radiobiological experiments, as well as the study of dose-response relationships on this proton beam. Another conclusion of this study is that Monte Carlo simulations can be used to help build preclinical lines in other setups.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34595122,

title = {Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer},

author = {Luc Ollivier and Maureen Labbé and Delphine Fradin and Vincent Potiron and Stéphane Supiot},

doi = {10.3389/fonc.2021.744679},

issn = {2234-943X},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Front Oncol},

volume = {11},

pages = {744679},

abstract = {Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32267172,

title = {Radiotherapy-induced overexpression of exosomal miRNA-378a-3p in cancer cells limits natural killer cells cytotoxicity},

author = {Joséphine Briand and Delphine Garnier and Arulraj Nadaradjane and Karen Clément-Colmou and Vincent Potiron and Stéphane Supiot and Gwenola Bougras-Cartron and Jean-Sébastien Frenel and Dominique Heymann and François M Vallette and Pierre-François Cartron},

doi = {10.2217/epi-2019-0193},

issn = {1750-192X},

year  = {2020},

date = {2020-04-08},

urldate = {2020-01-01},

journal = {Epigenomics},

volume = {12},

number = {5},

pages = {397--408},

abstract = { We here hypothesized that tumor-derived exosomal miRNA (TexomiR) released from irradiated tumors may play a role in the tumor cells escape to natural killer (NK) cells.  Our study included the use of different cancer cell lines, blood biopsies of xenograph mice model and patients treated with radiotherapy.  The irradiation of cancer cells promotes the TET2-mediated demethylation of miR-378 promoter, miR-378a-3p overexpression and its loading in exosomes, inducing the decrease of granzyme-B (GZMB) secretion by NK cells. An inverse correlation between TexomiR-378a-3p and GZMB was observed in murine and human blood samples.  Our work identifies TexomiR-378a-3p as a molecular signature associated with the loss of NK cells cytotoxicity via the decrease of GZMB expression upon radiotherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32293453,

title = {microRNAs identified in prostate cancer: Correlative studies on response to ionizing radiation},

author = {Maureen Labbé and Christianne Hoey and Jessica Ray and Vincent Potiron and Stéphane Supiot and Stanley K Liu and Delphine Fradin},

doi = {10.1186/s12943-020-01186-6},

issn = {1476-4598},

year  = {2020},

date = {2020-03-23},

urldate = {2020-01-01},

journal = {Mol Cancer},

volume = {19},

number = {1},

pages = {63},

abstract = {As the most frequently diagnosed non-skin cancer in men and a leading cause of cancer-related death, understanding the molecular mechanisms that drive treatment resistance in prostate cancer poses a significant clinical need. Radiotherapy is one of the most widely used treatments for prostate cancer, along with surgery, hormone therapy, and chemotherapy. However, inherent radioresistance of tumor cells can reduce local control and ultimately lead to poor patient outcomes, such as recurrence, metastasis and death. The underlying mechanisms of radioresistance have not been fully elucidated, but it has been suggested that miRNAs play a critical role. miRNAs are small non-coding RNAs that regulate gene expression in every signaling pathway of the cell, with one miRNA often having multiple targets. By fine-tuning gene expression, miRNAs are important players in modulating DNA damage response, cell death, tumor aggression and the tumor microenvironment, and can ultimately affect a tumor's response to radiotherapy. Furthermore, much interest has focused on miRNAs found in biofluids and their potential utility in various clinical applications. In this review, we summarize the current knowledge on miRNA deregulation after irradiation and the associated functional outcomes, with a focus on prostate cancer. In addition, we discuss the utility of circulating miRNAs as non-invasive biomarkers to diagnose, predict response to treatment, and prognosticate patient outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31906502,

title = {Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models},

author = {Karen Clément-Colmou and Vincent Potiron and Manon Pietri and Maëva Guillonneau and Emmanuel Jouglar and Sophie Chiavassa and Grégory Delpon and François Paris and Stéphane Supiot},

doi = {10.3390/cancers12010121},

issn = {2072-6694},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cancers (Basel)},

volume = {12},

number = {1},

abstract = {Background. The tumor vasculature acts as an interface for the primary tumor. It regulates oxygenation, nutrient delivery, and treatment efficacy including radiotherapy. The response of the tumor vasculature to different radiation doses has been disparately reported. Whereas high single doses can induce endothelial cell death, improved vascular functionality has also been described in a various dose range, and few attempts have been made to reconcile these findings. Therefore, we aimed at comparing the effects of different radiation fractionation regimens on the tumor vascular microenvironment.



METHODS: Lewis lung and prostate PC3 carcinoma-derived tumors were irradiated with regimens of 10 × 2 Gy, 6 × 4 Gy, 3 × 8 Gy or 2 × 12 Gy fractions. The tumor vasculature phenotype and function was evaluated by immunohistochemistry for endothelial cells (CD31), pericytes (desmin, α-SMA), hypoxia (pimonidazole) and perfusion (Hoechst 33342).



RESULTS: Radiotherapy increased vascular coverage similarly in all fractionation regimens in both models. Vessel density appeared unaffected. In PC3 tumors, hypoxia was decreased and perfusion was enhanced in proportion with the dose per fraction. In LLC tumors, no functional changes were observed at  = 15 days, but increased perfusion was noticed earlier ( = 9-11 days).



CONCLUSION: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30935573,

title = {Reoxygenation during radiotherapy in intermediate-risk prostate cancer},

author = {Stéphane Supiot and Caroline Rousseau and Mélanie Dore and Catherine Chèze-Le-Rest and Christine Kandel-Aznar and Vincent Potiron and Stéphane Guerif and François Paris and Ludovic Ferrer and Loïc Campion and Philippe Meingan and Grégory Delpon and Mathieu Hatt and Dimitris Visvikis},

doi = {10.1016/j.radonc.2018.12.022},

issn = {1879-0887},

year  = {2019},

date = {2019-04-01},

urldate = {2019-01-01},

journal = {Radiother Oncol},

volume = {133},

pages = {16--19},

abstract = {Hypoxia is a major risk factor of prostate cancer radioresistance. We evaluated hypoxia non-invasively, using F-Misonidazole PET/CT prior to radiotherapy and after a dose of 20 Gy in intermediate-risk prostate cancer patients. Decreased hypoxic volumes were observed in all patients, suggesting that radiotherapy induces early prostate tumor reoxygenation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31078733,

title = {Tumor vasculature remodeling by radiation therapy increases doxorubicin distribution and efficacy},

author = {Vincent Potiron and Karen Clément-Colmou and Emmanuel Jouglar and Manon Pietri and Sophie Chiavassa and Grégory Delpon and François Paris and Stéphane Supiot},

doi = {10.1016/j.canlet.2019.05.005},

issn = {1872-7980},

year  = {2019},

date = {2019-01-01},

urldate = {2019-01-01},

journal = {Cancer Lett},

volume = {457},

pages = {1--9},

abstract = {The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10 × 2 Gy and 2 × 12 Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29515786,

title = {Evaluation of tumor hypoxia prior to radiotherapy in intermediate-risk prostate cancer using F-fluoromisonidazole PET/CT: a pilot study},

author = {Stéphane Supiot and Caroline Rousseau and Mélanie Dore and Catherine Cheze-Le-Rest and Christine Kandel-Aznar and Vincent Potiron and Stéphane Guerif and François Paris and Ludovic Ferrer and Loïc Campion and Philippe Meingan and Gregory Delpon and Mathieu Hatt and Dimitris Visvikis},

doi = {10.18632/oncotarget.24234},

issn = {1949-2553},

year  = {2018},

date = {2018-02-01},

urldate = {2018-02-01},

journal = {Oncotarget},

volume = {9},

number = {11},

pages = {10005--10015},

abstract = {Purpose: Hypoxia is a major factor in prostate cancer aggressiveness and radioresistance. Predicting which patients might be bad candidates for radiotherapy may help better personalize treatment decisions in intermediate-risk prostate cancer patients. We assessed spatial distribution of F-Misonidazole (FMISO) PET/CT uptake in the prostate prior to radiotherapy treatment.



Materials and Methods: Intermediate-risk prostate cancer patients about to receive high-dose (>74 Gy) radiotherapy to the prostate without hormonal treatment were prospectively recruited between 9/2012 and 10/2014. Prior to radiotherapy, all patients underwent a FMISO PET/CT as well as a MRI and F-choline-PET. F-choline and FMISO-positive volumes were semi-automatically determined using the fuzzy locally adaptive Bayesian (FLAB) method. In FMISO-positive patients, a dynamic analysis of early tumor uptake was performed. Group differences were assessed using the Wilcoxon signed rank test. Parameters were correlated using Spearman rank correlation.



Results: Of 27 patients (median age 76) recruited to the study, 7 and 9 patients were considered positive at 2.5h and 3.5h FMISO PET/CT respectively. Median SUV and SUV tumor to muscle (T/M) ratio were respectively 3.4 and 3.6 at 2.5h, and 3.2 and 4.4 at 3.5h. The median FMISO-positive volume was 1.1 ml.



Conclusions: This is the first study regarding hypoxia imaging using FMISO in prostate cancer showing that a small FMISO-positive volume was detected in one third of intermediate-risk prostate cancer patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29482652,

title = {A new tissue segmentation method to calculate 3D dose in small animal radiation therapy},

author = {C Noblet and G Delpon and S Supiot and V Potiron and F Paris and S Chiavassa},

doi = {10.1186/s13014-018-0971-8},

issn = {1748-717X},

year  = {2018},

date = {2018-02-01},

urldate = {2018-02-01},

journal = {Radiat Oncol},

volume = {13},

number = {1},

pages = {32},

abstract = {BACKGROUND: In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Z) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Z) in small animal dose calculation.



METHODS: The method is based on the relationship found between CBCT number and ρ*Z product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZ variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZ method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations.



RESULTS: The study of the impact of ρZ variation over the range of materials, from ρZ = 2 g.cm (lung) to 27 g.cm (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZ method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance.



CONCLUSIONS: Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZ. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28536438,

title = {Optimizing radiotherapy protocols using computer automata to model tumour cell death as a function of oxygen diffusion processes},

author = {Perrine Paul-Gilloteaux and Vincent Potiron and Grégory Delpon and Stéphane Supiot and Sophie Chiavassa and François Paris and Sylvain V Costes},

doi = {10.1038/s41598-017-01757-6},

issn = {2045-2322},

year  = {2017},

date = {2017-05-23},

urldate = {2017-01-01},

journal = {Sci Rep},

volume = {7},

number = {1},

pages = {2280},

abstract = {The concept of hypofractionation is gaining momentum in radiation oncology centres, enabled by recent advances in radiotherapy apparatus. The gain of efficacy of this innovative treatment must be defined. We present a computer model based on translational murine data for in silico testing and optimization of various radiotherapy protocols with respect to tumour resistance and the microenvironment heterogeneity. This model combines automata approaches with image processing algorithms to simulate the cellular response of tumours exposed to ionizing radiation, modelling the alteration of oxygen permeabilization in blood vessels against repeated doses, and introducing mitotic catastrophe (as opposed to arbitrary delayed cell-death) as a means of modelling radiation-induced cell death. Published data describing cell death in vitro as well as tumour oxygenation in vivo are used to inform parameters. Our model is validated by comparing simulations to in vivo data obtained from the radiation treatment of mice transplanted with human prostate tumours. We then predict the efficacy of untested hypofractionation protocols, hypothesizing that tumour control can be optimized by adjusting daily radiation dosage as a function of the degree of hypoxia in the tumour environment. Further biological refinement of this tool will permit the rapid development of more sophisticated strategies for radiotherapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}