ESTRO 38 Abstract book

S21 ESTRO 38

Matiere,Villeurbanne, France ; 8 Harvard Medical School, Radiation Oncology, Boston, USA; 9 IWK Health Centre/Dalhousie University, Pediatrics/Pathology/Microbiology and Immunology, Halifax, Canada; 10 Dalhousie University/Nova Scotia Health Authority, Radiation Oncology/Physics and Atmospheric Science/Medical Physics, Halifax, Canada Purpose or Objective Nanoparticles made of high atomic number (Z) elements have been shown to sensitize cancer cells to radiation beams generated from linacs in vitro and in vivo . This effect occurs due to the emission of low energy photoelectrons and Auger electrons. Gold (GNP) and gadolinium (GdNP) based nanoparticles are biocompatible, and accumulate passively in tumours due to the enhanced permeability and retention effect, and there is growing evidence that localized radiation-induced tumour vascular damage can be used to clinical advantage. The introduction of low Z (sintered diamond) linac target instead of a standard Cu/W target results in a predicted 7.7 fold enhancement in the immediate proximity of the NP. The efficacy of combining the low Z target beam with NPs remains to be verified in vivo . To this end, we employed an established zebrafish xenotransplantation platform to quantify tumour cell proliferation. The zebrafish model offers the advantages of using a transparent fish to allow in vivo monitoring of grafts, as well as enabling large sample sizes. Material and Methods Beam setup: The samples were irradiated using a standard 6 MV or a custom 2.5 MV/diamond target x-ray beam from a TrueBeam linac. The 2.5 MV/diamond beam was generated by 2.5 MeV electron beam incident upon a sintered diamond target in the carousel. (see figure) Cell line screen: Panc1 (pancreas), FaDu (hypopharynx), A673 (Ewing), MDA-MB-231 (breast), LNCaP (prostate), A549 (lung) were labeled in vitro with NPs. They were irradiated with 8 Gy using the low Z or conventional target beam. Proliferation was assayed using Alamar Blue. Xenograft assay: Cells were co-labeled in vitro with NPs and a lipophilic fluorescent dye. Labeled cells were injected into the yolk sac of dechorinated casper zebrafish embryos and irradiated 1 dpi (days post injection) with 8 Gy. Tumour viability was measured by a standard ex vivo proliferation assay at 3 dpi.

Conclusion In a proof of principle experiment, we have shown enhanced radiologic cell kill in low-Z target irradiation in xenografted NP labeled cells. We are in the process of testing the model in additional cells with plans to examine tumour response in adult fish model. OC-0056 Multiple strategies for resolving radiation- induced neurocognitive dysfunction C. Limoli 1 , M. Vozenin 2 , M. Acharya 3 1 University of California Medical Sciences I, Department of Radiation Oncology, Irvine, USA; 2 Radio‐ Oncology/CHUV, Department of Radiation Oncology, Lausanne, Switzerland; 3 University of California, Radiation Oncology, Irvine, USA Purpose or Objective The progressive and debilitating side effects manifesting as cognitive dysfunction, mood disorders and a range of persistent pathologies have long hampered the radiotherapeutic management of CNS malignancies. For decades this problem has plagued therapeutic outcomes, and has not been restricted to brain cancer cases, as systemic chemotherapy elicits similar adverse outcomes, problems that remain an unmet medical need. Here we will highlight multiple strategies for resolving these long- standing clinical problems. Material and Methods Work in our laboratories have focused on resolving many of these treatment-associated complications through a variety of stem cell based, genetic, pharmacologic and beam delivery strategies. Cranial transplantation of multiple stem cell types, systemic delivery of stem-cell derived exosomes, retrograde endocanabinoid blockade, microglial depletion, epigenetic modulation and ultra-high dose rate “FLASH” radiotherapy have all been used and characterized to provide significant relief from the normal tissue toxicities transpiring in the irradiated and/or chemotherapy treated brain. Results Cranial grafting of 5 different pluripotent or multipotent human stem cell types, or stem cell-derived exosomes grafted intrahippocampally or systemically have been found to completely resolve radiation and chemotherapy- induced cognitive dysfunction from 1-8 months after treatment. Multiple spontaneous exploration tasks designed to interrogate learning and memory, and other tasks used to quantify anxiety, depression and fear extinction, demonstrate conclusively that our selected interventions improve behavioral performance in multiple preclinical rodent models over extended post-treatment times. This long term relief is associated with a significant preservation of host neuronal morphology, protection of the microvasculature and attenuation of neuroinflammation. Similar results have been obtained with the cannabinoid receptor 1 (CB1) antagonist AM251,

Results Cells showed differential responses to being irradiated with standard or low-Z target beam in the presence of GNP or GdNP. Among the cell lines tested, FaDu cells were the most sensitive to NP mediated irradiation. In Panc1 xenografts, there was a statistically significant decrease in the surviving cell numbers in samples treated with low Z target beams.