Utilizing New-Generation EGFR Tyrosine Kinase Inhibitor as Radiosensitizer in the Treatment of Urinary Bladder Cancer

• Main Authors: Yu-Chieh Tsai, 蔡育傑
• Other Authors: 鄭安理
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/01747075121732497583

博士 === 國立臺灣大學 === 臨床醫學研究所 === 103 === 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.