Radiosensitization effect of Sorafenib in hepatocellular carcinoma treatment

• Main Authors: John Chun-Hao Chen, 陳均豪
• Other Authors: Jeng-Jong Hwang
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/tde262

博士 === 國立陽明大學 === 生物醫學影像暨放射科學系 === 106 === Sorafenib alone has been established as one of the standard treatment for advanced hepatocellular carcinoma, but the overall prognosis remains poor. Therefore, other treatment modalities such were widely investigated in many studies, including the combination of Sorafenib and radiation therapy. Although some promising results were reported, unexpected adverse effects of targeted therapeutics combined with radiation therapy were also observed. An undefined and rarely-reported skin reaction was observed in 2 patients with advanced hepatocellular carcinoma who underwent concurrent Sorafenib and radiation therapy. We describe this phenomenon as Sorafenib induced radiation in-field skin (SIRIS) reaction, and the clinical course and radiation dosimetry of these patients were retrospectively reviewed. The development of SIRIS reaction was primarily limited within the radiation treatment fields, and it occurred at a relatively low dose during the courses of radiotherapy. The SIRIS reaction progressed in a radiation dose-dependent manner and was recovered spontaneously after 3–4 weeks of radiation therapy. The SIRIS reaction implicates a unique phenomenon that systemic skin reaction of targeted therapeutics, such as Sorafenib, might be limited or exacerbated in specific regions by local radiation therapy. According our previous reports, the radiosensitizing effect of Sorafenib was related to the suppression of NF-κB signal pathway, and further in vitro and in vivo studies were investigated to determine which combination of radiation and Sorafenib was most optimal. Huh7/NF-κB-tk-luc2/rfp cell line was established in our study, in which NF-κB indicates a NF-κB promoter, was utilized to noninvasively monitor the expression of NF-κB overtime in vitro and in vivo. The results show that pretreatment of sorafenib with RT suppresses the expressions of NF-κB and its downstream proteins induced by radiation through downregulation of phosphorylated extracellular signal-regulated kinase (pERK) most significantly compared with other treatment schedules. The results were further verified with Western blotting, electrophoretic mobility shift assay (EMSA), and NF-κB molecular imaging. The findings from our in vitro, in vivo and clinical studies suggest that Sorafenib demonstrates a radiosensitizing effect in HCC treatment when combined with radiation therapy, as some rarely seen clinical symptoms such as the SIRIS reaction was also exacerbated in this combination treatment.