ESTRO 2021 Abstract Book

S38

ESTRO 2021

Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; 5 German Cancer Research Center (DKFZ), Radiooncology/Radiobiology, Heidelberg , Germany; 6 National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; 7 German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), partner site Dresden, DKFZ, DKTK, Heidelberg and Dresden, Germany; 8 Helmholtz-Zentrum Dresden - Rossendorf, -, Dresden, Germany; 9 National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Heidelberg, Dresden, Germany; 10 German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Dresden, -, Dresden, Germany; 11 OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; 12 Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, -, Dresden, Germany Purpose or Objective The hypoxic cell sensitizer Nimorazole in combination with radiotherapy has been shown to confer treatment benefit in head and neck squamous cell carcinoma (HNSCC) patients. However, due to heterogeneity and extent of tumor hypoxia, biomarkers are needed in order to improve patient stratification and treatment. Purpose: To evaluate the therapeutic response of fractionated radiochemotherapy (RCTx) with Nimorazole in HNSCC tumor models for further identification of putative predictive biomarkers. Materials and Methods HNSCC xenografts were generated by injection of FaDu, SAS, UT-SCC-5, UT-SCC-8, Cal33 and SAT cells into NMRI (nu/nu) mice. Irradiations were performed with 30 fractions in six weeks combined with weekly cisplatin and Nimorazole. Pimonidazole hypoxic volume was determined. Nanostring gene expression analysis was performed in whole tumors and laser-microdissected hypoxic and normoxic samples from untreated xenografts. Results Nimorazole significantly increased Tumor control rate (TCR) in FaDu, SAS, UT-SCC-5 and UT-SCC-8 models and reduced the pimonidazole hypoxic volume after RCTx, when compared to RCTx with carrier (p<0.05). Conversely, SAT and Cal33 showed no differences on TCR and hypoxic volume after treatment. Gene expression analysis showed a significant increase of hypoxia-induced genes in the hypoxic areas of all tumor models (p<0.001). Specific groups of genes were found differentially expressed in the hypoxic areas according to treatment response: 21 differentially expressed genes (DEGs) were found in responder models and 73 DEGs in non- responder models, while 20/73 genes overlapped in both groups. From the remaining 53 genes, 35 genes were downregulated and 18 upregulated in the hypoxic areas of non-responders and showed and enrichment in DNA repair pathways (p<0.05) and HIF-1 signaling (p<0.05), respectively. Interestingly, these genes showed distinctive expression patterns. Specifically, 35 genes were found to be differentially expressed when only hypoxic regions from responder and non-responder models were compared, while 12 genes were preferentially expressed at the normoxic areas of the these tumors. Additionally, 8 genes were differentially expressed in both, hypoxic and normoxic areas as well as in untreated whole tumor samples from responder and non-responder models (p<0.0001), indicating a potential as predictive biomarkers for the modified RCTx treatment. Remarkably, SOX2 and EHHADH altered expression levels were associated to the 50% local tumor control probability (TCD50) of the tumor models. Finally, TCGA data analysis revealed an association between altered SOX2 (p<0.0001) and EHHADH (p=0.0002) gene expression and patient outcome in HNSCC, suggesting an additional prognostic value of these genes. Conclusion The decreased hypoxic volume after RCTx with Nimorazole and pre-treatment alterations in SOX2 and EHHADH gene expression are putative predictive biomarkers for local tumor control in HNSCC. OC-0063 Role of microenvironment on the post-irradiation regenerative potential of salivary gland stem cells Y. Wu 1 , S. Pringle 2 , U. Brouwer 1 , X. Peng 1 , A. Vissink 3 , L. Barazzuol 1 , R.P. Coppes 1 1 UMCG, Biomedical Sciences of Cells & Systems and Radiation Oncology, Groningen, The Netherlands; 2 UMCG, Rheumatology and Clinical Immunology, Groningen, The Netherlands; 3 UMCG, Oral and Maxillofacial Surgery, Groningen, The Netherlands Purpose or Objective Radiotherapeutic treatment of head and neck cancer is accompanied by unavoidable co-irradiation of the salivary gland, often resulting in hyposalivation and consequential reduced quality of life. Irradiation of the salivary glands may also result in senescent, fibrotic, and chronically inflamed tissue. Although regenerative medicine may help to improve post-treatment salivary gland function, the microenvironmental changes may be unfavorable for the regenerative potential of tissue stem cells. Therefore, we investigated microenvironmental changes of the irradiated murine salivary gland, and their effect on the potency of salivary gland stem cells (mSGSCs). Materials and Methods See below Results After 15 Gy local irradiation of murine salivary glands, pilocarpine-induced salivary secretion progressively reduced. A reduction in gland weight and number of mucin and aquaporin-5 expressing acinar cells was observed, and inflammation and fibrosis detected. Next to this, an enhanced number of p21-expressing cells