ESTRO 2020 Abstract book

S1058 ESTRO 2020

using mouse models of oral mucositis and radiodermatitis. We evaluated the orthostatic response to CPh-1014 in dogs. Results Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced by either a single dose or fractionated irradiation regimens in in vivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. In contrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension in dogs. Conclusion CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer. PO‐1804 In silico model of radiation‐therapy damage to microvasculature of tissues surrounding tumour A. Cicchetti 1 , F. Laurino 2 , T. Rancati 1 , P. Zunino 2 1 Fondazione IRCCS Istituto Nazionale dei Tumori, Prostate cancer program, Milan, Italy ; 2 Politecnico di Milano, Laboratory for Modeling and Scientific Computing MOX, milan, Italy Purpose or Objective The late damage to many different tissues after radiotherapy is mediated by impairments on the blood vessels. These chronic effects are often a consequence of the acute damage on the smallest functional units of the vasculature . Thus, based on previous works on advanced mathematical models of microcirculation, we propose a computational model able to capture the interplay between the capillary bed (metarterioles, capillaries and post-capillary venules) and the interstitial tissue perfusion in a healthy organs exposed to RT. Material and Methods The model embraces enough of the fundamental physics regulating the tissue microenvironment. Indeed, it is suitable to describe also the functional effects of radiation-generated rective oxygen species (ROS) on the fluid balance at the microvascular level. Here, we take into account two of the main acute effects already discussed in the literature: a) the vasodilation, which is the main feature of the inflammatory response caused by radiation exposure and b) the enhanced permeability of the endothelial junctions to macromolecules (modelled in Kabacik et al, Oncotarget 2017). These two factors play a crucial role in the accumulation of fluid in the interstitial space which could lead to oedema, then to capillary or venules occlusions (less rigid than arterioles) and finally to the consequent parenchymal damage of the organs due to the lack of an appropriate level of nutrients. Results The implemented geometry describes the three functional units and their own characteristics in terms of radius, wall thickness and elasticity, membrane permeability and fluid viscosity (see Fig.1). The quantitative impact of RT on the capillary bed is represented by: (1) an increase in the vessel pressure, Pv, (32 to 12 mmHg vs the usual 30 to 10 mmHg) miming condition of vasodilation; (2) a step variation of the permeability coefficient, Lp, between 10^-15 (almost impermeable) and 10^-12 m^2sKg^-1 (effect of the ROS on the cleavage of VE-cadherin),;and (3) a fluid accumulation during treatment in the extravascular space, thus, an interstitial pressure, Pt, from the usual small negative values to +3mmHg (where 5 mmHg is the standard oedema value). The simulations were designed to represent different levels of inflammatory response and fluid extravasation which could

research on radiation pulmonary fibrosis is the lack of suitable animal models. Therefore, we investigates the effect of LXA 4 a clinically similar IR-induced lung damage model. Material and Methods To evaluate the effect of LXA 4 on IR-induced lung mouse model with X-rad320, histologic findings and related protein analysis were observed through Masson trichrome (MT), haematoxylin and eosin (H&E) staining, immunohistochemistry, qRT-PCR and western blot. Lung volume and functional changes were evaluated using the Micro-CT and Flexivent system. Results In our model, infiltration of inflammatory cells, collagen contents and the expression of α-SMA were increased over time after IR and, interestingly, the protein level of FPR2, a specific receptor of LXA 4 was significantly increased under IR. Administration of LXA 4 significantly inhibits immune cell recruitment at the lesion site of lung tissue by IR and pro-inflammatory cytokines and fibrotic protein (e.g., TGFb, IL-6, SMA and collagen) were decreased by LXA 4 and regulated the signaling for Smads and NF-kB. Also, it decreased IR-induced ROS production and the expression of ROS-related protein, NOX4. Normal lung volume by micro-CT image in LXA 4 -treated mice was higher compared to that in irradiated mice and LXA 4 significantly recovered the IR-induced impaired lung function in Flexivent assay. Additionally, treatment of antagonist, WRW4 for selective receptor of LXA 4 , FPR2 more increased the IR-induced lung damage. Conclusion Collectively, the data obtained in this study suggested that LXA 4 attenuated IR-induced lung damage and it could be a potent therapeutic drug for alleviating radiation-induced lung fibrosis. * This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government. (NRF-2017M2A2A7A02019612, 2017R1D1A1B03027881, 2019R1A2C2086448) PO‐1803 Preventing Radioinduced Injury by Topical Application of an Amifostine Metabolite‐Loaded Thermogel C. Clémenson 1 , W. Liu 1 , D. Bricout 2 , L. Soyez-Herkert 1 , C. Chargari 3 , M. Mondini 1 , R. Haddad 2 , X. Wang-Zang 2 , L. Benel 2 , C. Bloy 2 , E. Deutsch 4 1 Gustave Roussy, Inserm U1030, Villejuif, France ; 2 CleveXel Pharma, Life Science, Paris, France ; 3 Gustave Roussy, Radiotherapy Department, Villejuif, France ; 4 Gustave Roussy, Inserm U1030 and Radiotherapy Department, Villejuif, France Purpose or Objective Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. Material and Methods We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. We evaluated its efficacy for the prevention of radiation-related toxicities,