ESTRO 2020 Abstract book

S1061 ESTRO 2020

Poster: Radiobiology track: Radiobiology of stem cells (cancer and normal tissue)

Poster: Radiobiology track: Radiobiology of particles and heavy ions

PO‐1808 Effects of photon, carbon ion and ultraviolet radiation on human mesenchymal stem cells A. Rühle 1 , R. Lopez Perez 2 , J. Brauer 2 , R. Saffrich 3 , J. Debus 4 , A. Grosu 1 , N.H. Nicolay 1 , P.E. Huber 2 1 University Medical Center Freiburg, Department of Radiation Oncology, Freiburg, Germany ; 2 German Cancer Research Center dkfz, Department of Molecular Radiation Oncology, Heidelberg, Germany ; 3 Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany ; 4 University Hospital Heidelberg, Department of Radiation Oncology, Heidelberg, Germany Purpose or Objective Mesenchymal stem cells (MSCs) have been demonstrated to regenerate tissue injuries induced by ionizing radiation such as photon, particle and UV irradiation. However, the influence of the different types of ionizing radiation on the survival and stem cell characteristics of human MSCs are largely unknown. Material and Methods Human bone marrow-MSCs were derived from healthy volunteers and irradiated using 6 MeV photons, carbon ions (C12) and UV-B at an output range of 280-320 nm wavelength. Clonogenic survival and viability of MSCs were quantified after exposure to photon, C12 and UV irradiation, and the influence of different types of ionizing radiation on cellular morphology, adhesion, surface marker expression, migratory capabilities and the multi- lineage differentiation capacity was analyzed. Flow cytometry measurements were used to investigate cell cycle distribution and apoptosis levels of MSCs. Repair of radiation-induced DNA damage, DNA double strand breaks and cyclobutane pyrimidine dimers (CPDs) was evaluated by immunofluorescence and ELISA, respectively. Results MSCs exhibited a relative resistance to all investigated types of ionizing radiation, and survival was comparable to that of differentiated fibroblasts for photon treatment and superior for UV-B radiation. The relative biological effectiveness (RBE) values of MSCs after C12 irradiation were found to range between 2.0 and 3.1 at 10% survival. Cellular morphology, adhesion ability and surface marker expression remained largely unaffected in MSCs even after high doses irrespective of the type of radiation. However, while the MSCs’ migratory capacity was preserved after photon and C12 irradiation, UV-B treatment significantly reduced cellular velocity of MSCs. The stem cells’ differentiation ability along the adipogenic, osteogenic and chondrogenic lineages was preserved after all forms of ionizing radiation, and expression of defining stem cell surface markers of MSCs was unaffected. Photon, C12 and UV irradiation resulted in a G2 phase cell cycle arrest and low apoptosis levels of MSCs. γH2AX foci as a marker for DNA double-strand breaks were efficiently repaired after photon and C12 irradiation. Similarly, repair of UV-B- induced CPDs was found to be more efficient in MSCs than in dermal fibroblasts. Conclusion This comparative analysis demonstrated that MSCs are relatively resistant to different types of ionizing radiation. The differentiation capacity as important prerequisite for the stem cells’ regenerative abilities remains largely intact after exposure to photon, C12 and UV-B irradiation. An efficient repair of radiation-induced DNA damage may contribute to the observed resistance.

PO‐1809 Parallel quantification of MR signal and radioenhancement of Gd nanoparticles for MR‐based dosimetry P. Maury 1 , M. Shahin 1,2 , A. Darricau 2,3 , S. Ammari 4 , F. Lux 5 , O. Tillement 5 , A. Rouyar-Nicolas 2 , C. Chargari 2,6 , E. Deutsch 2,6 , S. Lacombe 1 , C. Robert 2,3 , E. Porcel 1 1 Institut des Sciences Moléculaires d'Orsay ISMO, Paris Sud/Paris Saclay University, Orsay, France ; 2 Institut Gustave Roussy IGR, U1030 Molecular Radiotherapy, Villejuif, France ; 3 Institut Gustave Roussy IGR, Department of Medical Physics, Villejuif, France ; 4 Institut Gustave Roussy IGR, Department of Diagnostic Radiology, Villejuif, France ; 5 Institut Lumière Matière ILM, Claude Bernard University, Villeurbanne, France ; 6 Institut Gustave Roussy IGR, Department of Radiotherapy, Villejuif, France Purpose or Objective Several formulations of heavy metal based radiosensitizing nanoparticles (NPs) are in development. While increasing locally the energy deposit, these nanoparticles are posing the challenge of dose quantification. Gadolinium based NPs (AGuIX®) are currently developed as theranostic tools. These nanoagents accumulate in the tumor and act as radio-enhancers and MRI contrast agents. The objective of the ongoing project is to conduct a parallel NP concentration response assessment of MRI T1 relaxation and irradiated tumor cell killing. These measures are prerequisites for precise MRI based assessment of radiation cell kill increase by NP. Material and Methods First, a calibration curve giving the relaxation time modification (T1 mapping) of the MR signal as a function of the concentration of AGuIX® was established using an Eurospin T05 phantom. The AGuIX® concentration inside the tumor, based on MR images of three patients enrolled in a clinical trial combining the NPs to chemoradiation- brachytherapy in cervix cancer, was then determined. Moreover, 3D tumor models were prepared. There were composed of HeLa cells embedded in collagen. These models were incubated with AGuIX® following different conditions of time and concentration. Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) was performed on the 3D models to quantify the AGuiX® content and determine which combination allowed to reproduce at best NP concentration evaluated in the patients. The models were finally irradiated with a 6MV rotational beam or a High Dose Rate (HDR) 192 Ir source, with increasing doses from 1 to 6 Gy. Survival curves were established to quantify the increase of the biological effect of this new therapeutic combination. Results A monotonous relation between AGuIX® concentration and T1 relaxation times was obtained (Figure 1). Mean tumor concentrations varying between 47 and 81µmol/L were determined for the three patients. Incubation of the 3D models with AGuIX® concentration of 0.5mmol/L during 4h allows to reproduce at best NP tumor concentrations encountered in the clinical trial. Results of the first irradiations showed a neat amplification effect in presence of nanoparticles when the 3D models were irradiated with a 6MV source (Figure 2). At 2Gy, the enhancement ratio was about 69%.