ESTRO 2020 Abstract book

S26 ESTRO 2020

adjuvant radiotherapy[SA1] . The lack of effective treatments for or prevention of this debilitating neuronal toxicity not only compromises optimal treatment, but also leaves cancer survivors with significant disability. Here, we sought to investigate the biological role and underline molecular mechanisms of sirtuin 2 (SIRT2) in cisplatin neurotoxicity. Material and Methods Genetic murine models were utilized to compare the development of cisplatin-induced peripheral neuropathy in transgenic Sirt2 knock-in ( Sirt2 -KI) mice versus wild-type (WT) mice. The hyperalgesia seen in neuropathy was measured in terms of mechanical and thermal thresholds. Immunostaining and western blot were used to monitor SIRT2 expression in dorsal root ganglion (DRG) sensory neurons. The efficiency of DNA damage repair via nucleotide excision repair (NER) was examined using a dual-luciferase reporter assay, while neuronal cytotoxicity was determined using trypan blue staining assay. In addition to the genetic approach, the function of SIRT2, an NAD + deacetylase, was pharmacologically modified to validate its role in prevention and treatment of cisplatin- induced neuropathy. Results High expression of SIRT2 in Sirt2 -KI mice produces significant resistance to cisplatin-induced neuropathy compared to WT mice. Cisplatin provoked a nuclear translocation of SIRT2 in DRG sensory neurons, protecting mice against neuropathy. Overexpression of SIRT2 resulted in significantly improved cultured neuronal cell survival through the promotion of nucleotide excision repair of cisplatin-induced DNA crosslinks. In vivo inhibition of NER abolished SIRT2-mediated neuroprotection as evidenced by reductions in mechanical and thermal hyperalgesia thresholds. Finally, administration of nicotinamide riboside activated SIRT2 and prevented cisplatin-induced SIRT2 prevents cisplatin-induced neuron injury by regulating the NER pathway. Identification of this novel function warrants future investigation of nicotinamide riboside-mediated neuroprotection during platinum-based cancer treatment. PD-0064 Radiosensitive possibility of adipose-derived mesenchymal stem cells on hepatocellular carcinoma neuropathy. Conclusion PD-0065 Utilizing a high-throughput approach to identify effective agents for aggressive thyroid cancer A.S.R. Mohamed 1 , Y. Henderson 2 , Y. Chen 2 , C. Stephan 3 , G. Cote 4 , M. Cabanillas 4 , M. Zafereo 2 , V. Sandulache 5 , S. Lai 2 1 UT MD Anderson Cancer Center, Radiation Oncology, Houston- TX, USA ; 2 UT MD Anderson Cancer Center, Head and neck surgery, Houston- TX, USA ; 3 Center for Translational Cancer Research- Institute of Biosciences and Technology- Texas A&M University, Translational Cancer Research, Houston, USA ; 4 UT MD Anderson Cancer Center, Endocrine Neoplasia and Hormonal Disorders, Houston- TX, USA ; 5 Baylor College of Medicine, Department of Otolaryngology-Head & Neck Surgery, Houston, USA Purpose or Objective Despite the use of aggressive multimodality treatment, most anaplastic thyroid cancer (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibition has been recently approved for use in ATC, it remains effective in a minority of patients who ultimately develop drug resistance. We aim to identify effective agents against aggressive thyroid carcinoma (TC). Material and Methods Abstract withdrawn

Purpose or Objective ATR is an apical kinase in the DNA damage response (DDR). ATR inhibitors (ATRi) are currently in phase I clinical studies as monotherapy and as novel radiosensitizers [1]. Our group has previously observed marked changes in the immune tumor microenvironment after combined ATRi and radiation therapy (RT) [2]. Material and Methods We analysed gene expression in paired tumor biopsies from 5 patients participating in the phase I study of the ATR inhibitor AZD6738 as monotherapy or in combination with palliative radiotherapy. Paired biopsies from three patients with RECIST partial response (PR) and 2 patients with stable disease (SD) after ATRi monotherapy (dose escalation 40 to 240 mg twice daily) were analysed, as well as paired plasma cytokine levels in 11 patients treated with ATRi and 5 with ATRi + RT (20-80 mg twice daily with 20 Gy in 10 fractions). Results Significant increases in plasma CCL2 and CCL3 were observed after 2 weeks of ATRi monotherapy. We observed variable cytokine responses to ATRi + RT. Generally, there was an increase in CCL2 and CCL3 and a decrease in CCL5 with combination therapy. Increased CCL3 had also been observed in the supernatant of cell lines treated with this combination. Modulation of immune-related gene transcripts after treatment with ATRi was noted in paired tumour biopsies. Large increases were seen in macrophage- related transcripts. Interestingly, the patients who had partial responses to ATRi appeared to have larger increases in macrophage-related transcripts than those who had stable disease. This parallels the significant increase in myeloid cells that was observed in the animal model treated with ATRi-RT. Conclusion This work provides evidence that immunomodulation by ATRi ± RT observed in animal models also occurs in patients. Ongoing work aims to characterize this further in a larger number of patients, and correlate with tumor response. The observation that responding patients appear to have increased macrophage infiltration warrants further investigation. Funding National Institute for Health Research RM/ICR Biomedical Research Centre, Cancer Research UK CRUKD/14/007 References 1. PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours. Clin Transl Radiat Oncol, 2018. 12 : p. 16-20. ATR Inhibition Potentiates the Radiation- induced Inflammatory Tumor Microenvironment. Clin Cancer Res, 2019. 25 (11): p. 3392-3403. PD-0063 SIRT2 prevents cisplatin-induced peripheral neuron injury by enhancing nucleotide excision repair S. Acklin 1 , M. Zhang* 1 , W. Du* 1 , S. Jin 1 , F. Xia 1 1 University of Arkansas for Medical Sciences, Department of Radiation Oncology, Little Rock, USA Purpose or Objective Radiation and chemotherapy-induced neuropathy are some of the most common causes of dose reduction and discontinuation of cancer treatment, and often cause a major permanent impairment of quality of life in cancer patients. Furthermore, chemotherapy-induced neuropathy acts as a risk factor for development of radiation-induced neuropathy in patients receiving concomitant or 2.