ESTRO 2021 Abstract Book

S1642

ESTRO 2021

observed, whereas HCR varied from ~20 to 65. BE-43547 and TH-302 were not able to fully sterilize anoxic incubated spheroids exposed to 100 nM drug for 24h. Conclusion BE-43547 is highly hypoxia-selective and, unlike TH-302, displays no inter-cell line variability in potency or selectivity, which is highly encouraging for possible clinical application. Results suggests that BE-43547 directly targets a fundamental feature/target that is only present during hypoxia or only of survival importance during hypoxia. Spheroid experiments suggests that inappropriate tissue penetrability may be an obstacle, but this may be overcome by designing novel drug analogues once the target has been identified.

Digital Poster: Immuno-radiobiology

PO-1926 Enhanced local tumour control by combining proton radiation and immunotherapy M. Horsman 1 , S. Nielsen 1 , M. Sitarz 2 , M. Høyer 2 , B. Sørensen 2 1 Aarhus University Hospital, Experimental Clinical Oncology-Department of Oncology, Aarhus N, Denmark; 2 Aarhus University Hospital, Danish Centre for Particle Therapy, Aarhus N, Denmark Purpose or Objective Numerous pre-clinical studies have demonstrated the benefit of combining immunotherapy with photon irradiation. The aim of the current study was to investigate the potential anti-tumour action of combining immunotherapy with protons. Materials and Methods Male CDF1 mice were inoculated on the right rear foot with a C3H mammary carcinoma. Treatments started when tumours reached a volume of 200 cubic mm and involved restraining non-anaesthetised mice is specially constructed lucite jigs, exposing the tumour bearing legs and loosely attaching the leg to the jig with tape before leg immersion in a water-bath. Radiation, from a research fixed beamline, was delivered to tumours only, with the remainder of the animal being shielded. Single radiation fractions were given in an 83-107MeV pencil scanning proton beam in the center of a 3 cm spread out Bragg peak. Following irradiation (day 0) mice were given intraperitoneal injections with either PBS, anti-CTLA-4 or anti-PD-1 antibodies (10 mg/kg) administered on days 1, 4, 7, and 10. The endpoints were tumour growth time (TGT3; time for tumours to grow to 3 times the treatment volume) or local tumour control (percentage of mice showing local tumour control 90 days after treatment). Statistical comparisons involved a Student’s T-test (tumour growth) or a Chi-squared test (tumour control); significance level of p<0.05 for both. Results Control untreated tumours had a mean (with 1 S.E.) TGT3 of 4.3 days (3.8-4.8). No significant change was found following treatment with anti-CTLA-4 or anti-PD-1, the respective TGT3 values being 3.9 days (3.8-4.0) and 3.8 days (3.1-4.5). With radiation alone, a linear increase in TGT3 was seen with increasing radiation doses (5-20 Gy), reaching a value of 17.7 days (17.0-18.4) with 20 Gy. Anti-CTLA-4 had absolutely no effect on radiation doses up to 15 Gy, but there was a significant increase with 20 Gy; the TGT3 value being 22.4 days (21.2-23.6). To investigate the effect at higher radiation doses we performed a tumour control assay producing a dose response curve between 35 to 60 Gy. Following logit analysis of this curve, the TCD50 value (radiation dose causing tumour control in 50% of treated animals), with 95% confidence intervals, was found to be 51 Gy (49-53) for radiation only. This was significantly decreased to 45 Gy (38-52) when animals were also treated with anti-CTLA-4. However, anti-PD-1 did not significantly enhance radiation response; the TCD50 being 48 Gy (44- 53). Conclusion Checkpoint inhibitors alone had absolutely no effect on the growth of this C3H mammary carcinoma, but they did enhance the tumour response to proton irradiation. However, this enhancement appears to be dependent on the checkpoint inhibitor used and the radiation dose applied. Supported by grants from the Danish Cancer Society and the Danish Council for Independent Research: Medical Sciences. PO-1927 Disulfiram radiosensitizes hypoxic human colorectal cancer through inhibition of PHGDH M. Van De Gucht 1 , I. Dufait 2 , H. Jiang 3 , C. Corbet 4 , S. de Mey 5 , H. Wang 6 , H. Vandenplas 7 , K.L. Law 8 , T. Gevaert 9 , O. Feron 10 , M. De Ridder 11 1 Vrije Universiteit Brussel, Translational radiation oncology, physics and supportive care, Brussels , Belgium; 2 Vrije Universiteit brussel, Translational radiation oncology physics, ands supportive care, Brussels, Belgium; 3 Vrije universiteit brussel, translational radiation oncology physics, and supportive care, Brussels, Belgium; 4 Universiteit catholique de louvain (UCL), Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium; 5 vrije universiteit brussel, translational radiation oncology physics ,and supportive care, brussels, Belgium; 6 Vrije universiteit brussel, translational radiation oncology physics, and supportive care, brussels, Belgium; 7 vrije universiteit brussel, translational radiation oncology physcis ,and supportive care, brussels, Belgium; 8 vrije universiteit brussel, translational radiation oncology physics and supportive care, brussels, Belgium; 9 Vrije Universiteit Brussel, Department of Medical Oncology, Brussels, Belgium; 10 Universite catholique de Louvain (UCL), Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels, Belgium; 11 Vrije Universiteit Brusse, translational radiation oncology physics and supportive care, brussels, Belgium Purpose or Objective Repurposing of drugs has captured considerable attention in the pursuit of novel anticancer drugs. Disulfiram (DSF) is a widely used FDA approved anti-alcoholic drug, which exhibits anticancer properties alone or in combination with Copper (Cu). Although multiple mechanisms of action have been described, a novel mechanism recently was defined. DSF has been shown to target phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme of de novo serine biosynthesis pathway. End-metabolites of the pathway, such as glutathione, NAD(P)H, … are already known to interplay with radiotherapy. Accordingly, we asked whether DSF/Cu could synergize with radiation in human colorectal cancer. Materials and Methods Digital Poster: Radiation and tumour metabolism