ESTRO 2021 Abstract Book

S1643

ESTRO 2021

Human colorectal cancer cell lines HCT 116 and DLD1 were evaluated for the expression of serine synthesis pathway enzymes in both normoxic and hypoxic conditions. We assessed the inhibitory activity of DSF alone and in combination with Cu on PHGDH enzyme. Further, the radiomodulatory and metabolic effects of DSF alone and in combination with Cu were assessed, in both aerobic and hypoxic conditions at non-toxic doses. Results DSF/Cu radiosensitized hypoxic human colorectal cancer cells in 2D monolayer culture, 3D tumor spheroids, while leaving intrinsic radiosensitivity unaffected. Radio-modulatory effect was achieved by dysfunction in mitochondrial energy metabolism supported by decreased aKG and oxygen consumption rate. In order to obtain detailed metabolic profile, additional assays to are ongoing. Conclusion To best of our knowledge, the radiomodulatory effect of radiation combined with DSF/Cu through modulation of serine synthesis pathway via PHGDH inhibition has not been studied yet. Firstly, our preliminary results demonstrated that DSF/Cu hinders the enzymatic activity of PHGDH. Additionally, DSF/Cu radiosensitized hypoxic human colorectal cancer cells through disfunction of the mitochondrial energy metabolism. Further investigations regarding disruption in metabolic profile are ongoing. In vivo confirmation is still necessary. 1 Vrije universiteit brussel, translational radiation oncology, physics ands supportive care, brussels, Belgium; 2 Vrije Universiteit Brussel, translational radiation oncology physics, and supportive care, Brussels, Belgium; 3 Vrije Universiteit Brussel, Translational radiation oncology physics and supportive care, Brussels, Belgium; 4 Vrije Universiteit Brussel, translational radiation oncology physics and supportive care, Dilbeek, Belgium; 5 université catholique de louvain, Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), , Brussels, Belgium; 6 vrije universiteit brussel, translational radiation oncology physics and supportive care, Brussels, Belgium; 7 Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Department of Medical Oncology, Brussels, Belgium; 8 université catholique de louvain, Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium; 9 vrije universiteit brussel, translational radiation oncology physics and supportive care, Dilbeek, Belgium Purpose or Objective Augmented serine synthesis activity is increasingly apparent in distinct types of cancers, and was first described in triple negative breast cancer. Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in serine biosynthesis and its overexpression is associated with higher tumor grade, shorter relapse time and decreased overall survival. Downstream metabolites of the serine biosynthesis already demonstrated to be implicated in radiomodulatory response in cancer. Hence, the interplay between reprogramming of metabolic pathways and radiation can potentially improve therapeutic outcome. Therefore, we asked whether inhibition of serine synthesis pathway could improve the radioresponse in human colorectal cancer. Materials and Methods Human colorectal cancer cell lines HCT 116 and DLD1 were evaluated for the expression of serine synthesis pathway enzymes in both normoxic and hypoxic conditions. Additionally, the influence of extracellular serine availability on expression levels was assessed. We examined the radiomodulatory and metabolic effects of PHGDH inhibition, by using NCT- 503, in both aerobic and hypoxic conditions at non-toxic doses. Results PHGDH inhibition radiosensitized hypoxic human colorectal cancer cells in 2D monolayer culture, 3D tumor spheroids, while leaving intrinsic radiosensitivity unaffected. Radio-modulatory effect was achieved by dysregulation of ROS homeostasis and dysfunction in mitochondrial energy metabolism supported by decreased aKG and oxygen consumption rate. In vivo radiation experiments in HCT 116 xenograft are ongoing. Conclusion To best of our knowledge, the combination of serine modulation and radiation has not been studied so far. Our results demonstrated that modulation of serine cooperates with radiation and radiosensitizes hypoxic human colorectal cancer through dysfunction of mitochondrial energy metabolism and disrupted ROS homeostasis. Further investigation relating availability of extracellular serine and the dependence of this latter in cancer is necessary, as well as in vivo confirmation of this phenomenon. PO-1928 Radiation cooperates with modulation of serine in human hypoxic colorectal cancer cells. M. Van De Gucht 1 , I. Dufait 2 , E. Demesmaeker 3 , H. jiang 4 , C. Corbet 5 , S. de Mey 6 , H. Vandenplas 6 , K.L. Law 6 , T. Gevaert 7 , O. Feron 8 , M. De Ridder 9 PO-1929 Identification of DNA repair-based biomarkers related to treatment outcome in head and neck cancers G. Muggiolu 1 , S. Libert 2 , B. Treillard 1 , G. Alfonse 3 , P. Philouze 4 , C. Rodriguez-Lafrasse 5 , A. Lauret 6 , P. Ceruse 7 , C.A. Righini 8 , S. Sauvaigo 1 1 LXRepair, Research & Development, La Tronche, France; 2 LXRepair, Research & development, La Tronche, France; 3 Hospices Civils de Lyon, Biochemistry and Molecular Biology, Pierre-Bénite, France; 4 Hospices Civils de Lyon, Head Neck , Lyon, France; 5 Hospices Civils de Lyon, Biochemistry and Molecular Biology , Pierre-Bénite, France; 6 CNRS/UMR 5822, Cellular and Molecular Radiobiology , Oullins Cedex, France; 7 Hospices Civils de Lyon, Head Neck, Lyon, France; 8 Michallon Hospital, Head Neck Surgery , Grenoble, France Purpose or Objective Biomarkers have several roles for clinical applications in cancer: a) improving diagnosis, b) predicting clinical outcomes, c) stratify patients to personalize the treatment. Head and neck cancers (H&N) are cumbersome pathologies for which improvements in diagnosis, treatment choice and treatment side-effects risk prediction, are needed. Given the essential role of DNA repair machinery in determining the resistance and the toxicity of cancer treatments, we conducted a prospective clinical proof-of-concept aimed at identifying relevant DNA repair-based biomarkers. The Digital Poster: DNA damage response