2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/651263摘要：食道癌為一高致死率疾病。在台灣，食道癌為死亡人數上升比例最高的癌症, 其中 95 %為食道鱗狀上皮細胞癌(esophageal squamous cell carcinoma，ESCC)。ESCC 目前無標靶治療，病患在治療過後，時常伴隨著高風險的復發，五年存活率平均不到20%。先前執行一年期新進人員計畫發現，AXL 受體酪胺酸激酶的表現與ESCC 不良預後與復發有關，並且在有抽菸、吃檳榔的族群中有較高的表現。轉化生長因子TGF-1 具有可以誘發AXL 表現的潛力，而在其他癌症中，抽菸、喝酒、吃檳榔等不良習慣與TGF-1 的上升有關。因此，不良習慣可能藉由誘發TGF-1 上升，進而誘發AXL 的表現而導致ESCC 復發，然而此主題缺乏探討。先前也發現AXL 的非特異性抑制劑 Foretinib 可有效毒殺ESCC 細胞，因此AXL 與TGF-1 的抑制劑對ESCC 細胞的毒殺效果也值得探討。本2 年期計畫欲進一步探討TGF-1 與ESCC 病人之不良習慣、AXL 表現及腫瘤復發之相關性，並評估AXL 之專一性標靶藥物於ESCC 細胞之毒殺效果及作用路徑。研究目標如下:1) 研究 ESCC 組織與血清中TGF-1 的表現與AXL 表現量、不良習慣及腫瘤復發的關係。2) 探討 TGF-1 於正常與癌化食道細胞中是否能誘發AXL 表現及相關癌化作用。3) 分析AXL 之專一性標靶藥物R428 與 BMS-777607 於ESCC 細胞之毒殺效果與作用路徑。相信本研究可以提供ESCC 標靶治療珍貴的訊息，並接續先前的觀察，提供更深入的機轉探討。<br> Abstract: Esophageal cancer is a fast-growing deadly disease worldwide, including in Taiwan. Esophagealsquamous cell carcinoma (ESCC) accounts for 95 % of primary esophageal cancer. Without efficienttargeted drugs, ESCC patients are with poor prognosis and high risk of local recurrence/distantmetastasis even combining surgery and CCRT (concurrent chemo-radiotherapy). The average 5-yearsurvival of ESCC is less than 20%. We previously demonstrated that AXL receptor tyrosine kinase is astrong adervse prognostic factor and its expression is correlated with disease recurrence and distantmetastasis of ESCC. Interestingly, the AXL expression is more frequently observed in patients withunfavorable habits, such as smoking or betel-chewing. Transforming growth factor-1 (TGF-1) hasbeen demonstrated to induce the expression of AXL during langerhans cell differentiation. Meanwhile,TGF-1 were reported to elevated in patients with unfavorable habits, such as smoking, drinking andbetel-chewing, in other malignant diseases. Thus, unfavorable habits might induce tumor recurrencemediated by activate TGF-1 and AXL in ESCC, however, this topic are hardly investigated. We alsopreviously demonstrated a non-specific AXL inhibitor foretinib can induce ESCC cell death efficiently.Therefore, the efficacies of AXL inhibitors are worthy of systematically analyzed in ESCC cells. Incurrent 2-year project, we intend to further investigate the correlation of TGF-1 and unfavorable habits,AXL expression, as well as tumor recurrence of patients with ESCC. We will also evaluate theefficacies of AXL selective inhibitors in ESCC cells. The specific aims of the project will be:1) To detect the expression levels of serum and tissue TGF-1 of ESCC patients (n=200) and correlatedwith the expression of tissue AXL, disease recurrence and the unfavorable habits, including smoking,drinking, and betel-chewing of patients.2) To investigate whether TGF-1 induces expression of AXL and correlated cellular events totumorigenesis in normal esophageal cells and ESCC cells3) To evaluate the efficacies of the potent and selective inhibitors of AXL, such as R428 andBMS-777607, and involved functional pathways in ESCC cells.We believe this continuous study will provide valuable information for targeted therapy of ESCC,and further results of mechanistic analysis.食道癌食道鱗狀上皮細胞癌標靶治療AXL轉化生長因子TGF-1esophageal canceresophageal squamous cell carcinoma (ESCC)target therapyAXLTGF-1