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標題: | 利用新一代EGFR酪氨酸激酶抑制劑為放射增敏劑,用於膀胱癌的治療 Utilizing New-Generation EGFR Tyrosine Kinase Inhibitor as Radiosensitizer in the Treatment of Urinary Bladder Cancer |
作者: | Yu-Chieh Tsai 蔡育傑 |
指導教授: | 鄭安理,郭明良 |
關鍵字: | EGFR,HER2,放射治療,膀胱癌, EGFR,HER2,Radiotherapy,Bladder cancer, |
出版年 : | 2015 |
學位: | 博士 |
摘要: | 膀胱癌是全世界與台灣男性第九常見的惡性腫瘤。對許患有局部肌肉侵襲性膀胱癌的病人,標準的膀胱根除手術並不可行。許多研究的焦點放在如何在”膀胱保存”的治療基準下善用放射線治療。然而相較於膀胱根除手術,放射線治療肌肉侵襲性膀胱癌病人的長期存活率低了約10%。傳統上化學治療藥物被用來當成放射增敏劑,但這樣的治療有許多廣為人知的毒性。因此我們有很強大的需求尋找能夠增進膀胱癌放射治療效果,又不增加毒性的藥物。
一個可以增進膀胱癌放射治療效果的合理方法,是同時使用抑制放射治療相關信息傳導路徑的標靶藥物。表皮生長因子受體(EGFR)是其中最重要的。Cetuximab是一個抑制EGFR的單株抗體,它已被證明在頭頸癌病人身上併用放射治療,可以增加療效。至於膀胱癌,gefitinib是一個EGFR的酪胺酸激酶抑制劑,它被顯示在膀胱癌的細胞模式有中等的放射增敏效果,而在膀胱癌的活體模式則只有些微的放射增敏效果。因此這個主題值得後續的研究。 在前驅性研究中我測試了包括erlotinib (EGFR抑制劑)、trastuzumab (HER2抑制劑)和lapatinib (EGFR/HER2抑制劑) 在膀胱癌細胞的放射增敏效果,可惜沒有一個有好的發展潛力。反而是afatinib,一個新一代可以同時抑制EGFR和HER2的酪胺酸激酶抑制劑,比較有前途。 在老鼠膀胱癌模式中,我第一次展示了在膀胱癌的細胞及活體模式中,afatinib都是一個有效的放射增敏劑。這個部分的動物實驗是在免疫正常的老鼠體內進行,比較類似人類的生理狀態。Afatinib似乎抑制了放射活化的EGFR與HER2信息,並增加了細胞DNA傷害與凋亡。 基於以上的發現,我假設在膀胱癌細胞,同時抑制EGFR和HER2酪胺酸激酶活性的afatinib,相較於只抑制EGFR酪胺酸激酶活性的erlotinib,會有較佳的放射增敏性。 為了確認這個假說,第一代的EGFR酪胺酸激酶抑制劑erlotinib和第二代的afatinib,第一次在人類膀胱癌細胞中被拿來比較它們的放射增敏性。我展示了在人類膀胱癌的細胞及活體模式中erlotinib的放射增敏性的不足以及afatinib優越的放射增敏效果。在HER2被抑制的人類膀胱癌細胞中,可以看到erlotinib顯示了放射增敏效果,所以可能是因為EGFR和HER2對放射敏感性有協同作用,讓afatinib雙重抑制的特性才會變得有效。我也展示了對EGFR-HER2異源雙體的抑制可能是afatinib放射增敏性機轉的證據。 在”展望”中我提到如何繼續這個研究主題,以及怎樣應用到臨床上。我希望這個研究的結果可以協助達成”增進膀胱癌放射治療效果,又不增加毒性”的目標。 Bladder cancer is the ninth most common cancer in the world and in Taiwanese male population. For many patients with localized muscle-invasive bladder cancer, radical cystectomy is not a feasible treatment, and considerable interest was focused on the optimal use of radiotherapy in ”bladder preservation” protocol. However, the long-term survival of patients receiving radiation-based therapy in muscle invasive bladder cancer is about 10% inferior to patients receiving standard radical cystectomy. Traditionally chemotherapeutic agents are used as radiosensitizer but they have many well-known toxicities. Therefore, there is a strong need to find agents enhancing the radiation effect in urinary bladder cancer treatment while not increasing the toxicities. A reasonable way to enhance the outcome of radiotherapy is by concomitantly using agents that inhibit radiation-activated signaling pathways. Epidermal growth factor receptor (EGFR) is the most important target. Cetuximab, an anti-EGFR antibody, has shown clinical benefit in head and neck cancer when combined with radiotherapy. In bladder cancer, gefitinib, an EGFR tyrosine kinase inhibitor (TKI), has moderate in vitro and marginal in vivo radiosensitizing activities. Therefore the topic deserves further investigation. In pilot study, I tested the radiosensitizing activities of erlotinib (EGFR inhibitor), trastuzumab (HER2 inhibitor) and lapatinib (EGFR/HER2 inhibitor) in bladder cancer cells. None of them showed good potential. Instead, afatinib, a new-generation EGFR inhibitor with activity against both EGFR and HER2, is more promising. In murine bladder cancer model, I demonstrated for the first time the in vitro and in vivo radiosensitizing activity of afatinib, an EGFR/HER2 dual inhibitor. The animal study was performed in immunocompetent mice and mimic human physiologic status. Afatinib likely mediates its effect on bladder cancer cells by suppressing radiation-activated EGFR and HER2 signals and thereby causing enhanced DNA damage and cell apoptosis. Based on the findings I hypothesized that in bladder cancer cells, the concomitant inhibition of EGFR and HER2 tyrosine kinase activity by afatinib has greater radiosensitizing activity than the inhibition of EGFR tyrosine kinase activity alone by erlotinib To confirm the hypothesis, in human bladder cancer model the radiosensitizing effects of different generations of clinically useful EGFR TKIs were compared for the first time. I showed the inadequacy of EGFR inhibition alone and the advantage of concomitant blockade of radiation-activated EGFR and HER2 signaling to inhibit the in vitro and in vivo growth of bladder cancer cells. The radiosensitizing effect of an EGFR inhibitor was much higher in HER2 knocked-down than wild-type cells, therefore HER2 may play a synergistic role with EGFR in determining radiosensitivity. I also showed evidence to support that receptor heterodimerization plays an important role in the radiosensitizing effect of afatinib. In Prospect I mentioned how to continue current project and apply the data to clinical use. I hope that the results of this study can help to meet the need of enhancing the radiation effect in urinary bladder cancer treatment while not increasing the toxicities. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4405 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 臨床醫學研究所 |
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