新興膽管癌藥物研究

Abstract

膽管癌是一種高惡性度之侵襲性癌症，由於缺乏明顯症狀、診斷不易以及有限的藥物治療選 擇，造成膽管癌病人預後不佳，治療上帶來一個相當大的臨床挑戰。由於目前標準治療的療 效不盡理想，開發新型膽管癌的治療藥物無疑是一項重要使命。蛋白激脢是調節多種重要細 胞功能(如增殖和細胞代謝)的酵素，並且在發炎反應中扮演關鍵角色，而膽管細胞內的發炎反應是導致各種膽管癌亞型的主要風險。包括膽管癌在內的發炎性癌細胞中，signal transducers and activators of transcription 3 (STAT3)等激脢常常被過度活化，而蛋白激脢的活 性及其上下游相關的激脢均會受到磷酸脢的負向調控，這些磷酸脢負責激脢的去磷酸化，與 激脢的活性息息相關。與蛋白激脢相同，磷酸脢在調節細胞活動中也扮演著重要的角色，對 於多種細胞的功能至關重要。Serine/ threonine protein phosphatase 5 (PP5)，屬於磷蛋白磷酸 脢(PPP)家族當中，一種參與調節壓力信號和細胞增長的獨特磷酸脢。我們的研究專注於 抑制蛋白激脢或抑制磷酸脢的調控，藉以開發新型膽管癌治療藥物。在我們的兩個概念驗證 模型當中，展示了開發膽管癌新型治療劑的潛在機制。第一個模型顯示，藉由新型 Sorafenib 衍生物調控 SHP-1，抑制磷酸化的 STAT3 可以作為潛在的治療策略。第二個模型則發現， 通過調控 AMPK 來抑制 PP5，亦是一種可能的膽管癌治療途徑。我們衷心地希望透過這些 發現，能為未來膽管癌的治療藥物的研發盡上一份微薄貢獻。

Cholangiocarcinoma (CCA) is an aggressive disease with a dismal prognosis due to its silent presentation, delayed diagnosis, and limited effective treatment options. The significant unmet medical need in patients with CCA presents a substantial clinical challenge. Due to the unsatisfactory therapeutic outcomes associated with the current standard treatments, the development of novel agents for CCA treatment is undeniably an essential mission. Protein kinases, enzymes that regulate numerous essential cellular functions such as proliferation and cell metabolism, play a key role in inflammation, which represents the main risk factor shared by all CCA subtypes. Kinases such as signal transducers and activators of transcription 3 (STAT3) are frequently activated in inflammatory cancer cells including CCA. The activities of protein kinases and their upstream or down-stream kinases are negatively regulated by protein phosphatase, which are responsible for the dephosphorylation of these kinases. Similar to kinases, protein phosphatases play a fundamental role in regulating cellular activities, as protein phosphorylation and dephosphorylation are essential for a wide range of cellular functions. Serine/threonine protein phosphatase 5 (PP5), belong to the phosphoprotein phosphatase (PPP) family, is a unique phosphatase that participate in regulating stress signaling and cell growth. We focus on discovering new agents for CCA treatment not only regulating kinase but also phosphatase pathway. We focus on discovering new agents for CCA treatment through the inhibition of not only kinase but also phosphatase pathways. Our two proof-of-concept models demonstrate the potential mechanisms for developing novel therapeutic agents for CCA. The first model demonstrates that inhibiting phosphorylated STAT3 by a novel Sorafenib derivative, through the regulation of SHP-1, is a potential therapeutic strategy. The second model, on the other hand, suggests that targeting PP5A through the regulation of AMPK presents an appealing treatment pathway for CCA. We hope that our findings will pave the way for the development of new treatments for CCA in the future.