ESTRO 2020 Abstract Book

S26 ESTRO 2020

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.

Purpose or Objective Several studies have investigated strategies to improve the clinical efficacy of radiotherapy (RT) against hepatocellular carcinoma (HCC), yet the prognosis remains poor. Human adipose tissue-derived mesenchymal stem cells (AT-MSCs), easily accessible and abundant in quantity, have represented as an attractive therapeutic tool for the stem cell-based treatment for cancer diseases. In the present study, we performed multiple experiments to evaluate the anti-cancer potential of AT-MSCs combined with RT on HCC cell lines. Material and Methods Human AT-MSCs were isolated from the lipoaspirates of healthy donors undergoing elective liposuction. Two human HCC lines HepG2 and HuH7 were seeded. After incubation, the growth medium was replaced with non- conditioned control medium in the CTRL group, non- conditioned control medium followed by different doses of radiation in the RT group, AT-CM in the MSC group, or different doses of radiation followed by AT-CM in the RTM group. Cell proliferation, colony formation, sphere formation, wound healing, migration and invasion assays was analysed. For in vivo experiments, 5-week-old nude mice were injected subcutaneously with Huh7 cells. After the tumour volume reached ~100 mm3, the animals were randomized into four groups. RNA sequencing and high- throughput analysis were assessed to underlie the mechanisms in the synergistic effects of AT-MSCs and RT combination treatment. Results Through direct co-culture and indirect separate culture experiments, we showed that AT-MSCs could enhance inhibitory effect of RT on reducing HCC cell growth, migration and invasion in both in vitro and in vivo experiments. RNA-sequencing analysis revealed a noticeable interferon-induced transmembrane 1 (IFITM1) - induced tumour gene signature. Gain and loss of mechanistic studies indicated that mechanism was attributed to downregulated expression of STAT3 and MMPs and upregulated expression of P53 and caspases. Collectively, our findings suggest that AT-MSCs might enhance the therapeutic effects of RT on HCC, providing a rationale for AT-MSCs and RT combination therapy as a new remedy for HCC. Conclusion In conclusion, we showed for the first time that AT-MSCs enhanced the efficacy of radiotherapy in HCC cell in vitro and significant delaying the growth of HCC tumors in vivo, by silencing IFITM1 expression. 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

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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 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 L. WU 1 , Z. Sun 2 , Q. Tang 1 , X. Yin 1 , J. Xin 2 , Q. Pan 2 , S. Yan 1 1 First affiliated hospital- Zhejiang university school of medicine, Radiation oncology, Hangzhou, China ; 2 First affiliated hospital- Zhejiang university school of medicine, State key laboratory for diagnosis and treatment of infectious diseases, Hangzhou, China neuropathy. Conclusion