2015-08-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/663164摘要：膀胱癌是最常見的泌尿癌之一。相較於膀胱根除手術，肌肉侵襲性膀胱癌病人若是接受放射為基 礎的治療，其長期存活率低了約10%。含順鉑的化學治療常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。對於眾多不願意摘除膀胱或身體狀況不適合開刀的病人而言，有很強大的需求 要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)是其中最重要之一。我在之前的科技部研究計晝已經顯示：同時阻斷 EGFR和HER2的酪胺酸激酶抑制劑，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，所以可在細胞及老鼠模式中增加膀胱癌細胞的放射敏感度。因此這種新型抑制劑有很 好的臨床潛力。在這個研究計晝中，我將基於之前的研究結果，繼續研究何以同時阻斷EGFR和HER2的酪胺 酸激酶抑制劑，可以增加膀胱癌細胞的放射敏感度。本計晝的特定目標有：目標一：探討HER2在膀胱癌EGFR媒介的放射保護效果中扮演的角色。初步的結果顯示:有anti-HER2 shRNA轉染的T24細胞株，是比控制組的T24細胞株對於erlotinib的放射增敏效果有更好的加強作用。目標二 ：瞭解HER2如何與EGFR作用增加膀胱癌細胞的放射感度。初步的結果顯示:放射線可增強EGFR和HER2間的異源二聚作用(heterodimerization)，而在放射之前 加入afatinib可減少這種效果。目標三：瞭解HER2如何由微環境以及上皮變間質型的轉換(EMT)影響EGFR媒介的放射保護作用。初步的結果顯示：亞致死劑量的放射線可增強膀胱癌細胞的侵略性，在放射之前加入afatinib則可減 少這種效果。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。<br> Abstract: Urinary bladder cancer is one of the most common urinary tract cancer. However, the long-term survival of patients receiving radiation-based therapy in muscle-invasive bladder cancer is about 10% inferior to patients receiving radical cystectomy. Cisplatin-containing chemotherapy is often used as radiosensitizer but it has many well-known toxicities. For many patient who are not willing or suitable to receive surgery, there is a strong need for agents to enhance 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 one of the most important. In my previous MoST grant I already demonstrated that a tyrosine kinases inhibitor which blocks EGFR and HER2 simultaneously can increase the radiosensitizing effect in bladder cancer cells in in vitro and mouse model. Radiation-activated EGFR and HER2 signaling were suppressed by afatinib with the enhanced DNA damage and apoptosis. Therefore this new inhibitor has a good clinical potential.In this project, based on my previous study results, I will continue to study why tyrosine kinase inhibitor which can block EGFR and HER2 simultaneously can increase the radiosensitizing effect in bladder cancer cells. For the specific aims:Aim 1: to explore the role of HER2 in EGFR-mediated radioprotection of urinary bladder cancer cells.The preliminary data showed that the radiosensitizing effect of T24 cells transfected with anti-HER2 shRNA was better than treated T24 cells transfected with scramble RNA when combined with EGFR inhibitor erlotinib.Aim 2: to understand how HER2 interact with EGFR in enhancing radiosensitivity of bladder cancer cells.The preliminary data showed that that the level of heterodimerization between EGFR and HER2 was enhanced by radiation, but the enhancement was inhibited by the combination of radiation and afatinib pretreatment.Aim 3: to understand how HER2 influence EGFR-mediated radioprotection in microenvironment and epithelial-mesenchymal transition (EMT).The preliminary data showed that sublethal irradiation promotes cancer cell invasion and afatinib inhibits radiation-induced invasiveness of bladder cancer cellsI hope that the results of this study can help to meet the need to enhance the radiation effect in urinary bladder cancer treatment while not increasing the toxicities.