Abstract 5085: SOCS-1 gene therapy combined with radiation therapy has a potent antitumor effect for esophageal squamous cell carcinoma
Authors: Takahito Sugase, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Koji Tanaka, Yashuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka
Journal: Cancer Research (2017)

Abstract INTRODUCTION Radiation therapy (RT) is one of the main strategies for esophageal squamous cell carcinoma (ESCC) besides surgery and chemotherapy. Although RT has shown remarkable clinical benefits for ESCC patients, there remains the resistance for RT. Recently, some reports show that STAT3 activation is induced by irradiation and can result in treatment-resistance for radiotherapy in various cancer. Suppressor of cytokine signaling-1 (SOCS-1) has been cloned as a negative regulator of various cytokine signaling. We previously reported that overexpression of SOCS-1 showed a potent anti-tumor effect for ESCC through targeting of JAK/STAT and FAK/ERK signaling pathway. Since these results, SOCS-1 might have a possibility to overcome the resistance of RT. The aim of this study is to evaluate the antitumor effect of SOCS-1 gene therapy using adenoviral vector (AdSOCS-1) combined with RT. METHODS At first, we evaluated RT resistance by the STAT3 in ESCC cell lines by using pEB-Multi-constitutive-STAT3(c-STAT3) vector. We examined the colony forming assay between parent (TE8, TE9, TE11, TE14) and stably expression of c-STAT3 cells. Next, we evaluated cell growth inhibition effect of AdSOCS-1 gene therapy combined with RT in vitro and in vivo. As in vivo model, we examined the combined effect of RT (2Gy) and AdSOCS-1 gene therapy by using TE14 xenograft mice (ICR nu/nu mice). RESULTS At first, ESCC cell with stably expression of c-STAT3 showed a significant increase in colony forming ability after RT as compared with parent and mock cell. It suggested that activation of STAT3 might be related to RT resistance in ESCC cell. Furthermore, ESCC cells with RT were induced the secretion of IL-6, and the activation level of STAT3 was elevated by multiple RT. In addition, they increased the expression of anti-apoptosis protein (mcl-1, survivin), and might have a RT resistance. Next, we confirmed that combination therapy with RT and AdSOCS-1 had better proliferation inhibitory effect and decreasing of colony forming ability. In addition, we showed that AdSOCS-1 gene therapy inhibited the induction of the expression of anti-apoptosis protein (mcl-1, survivin) by RT and induced apoptosis synergistically. As in vivo model, the combination therapy group showed a significant anti-tumor effect compared to the RT alone group and AdSOCS-1 gene therapy alone group. CONCLUSIONS The activation of STAT3 is involved in resistance to radiation therapy in esophageal squamous cell carcinoma, and SOCS-1 gene therapy combined with radiation therapy may have a potent anti-tumor effect. Note: This abstract was not presented at the meeting. Citation Format: Takahito Sugase, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Koji Tanaka, Yashuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka. SOCS-1 gene therapy combined with radiation therapy has a potent antitumor effect for esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5085. doi:10.1158/1538-7445.AM2017-5085