2011-05-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/655716摘要：本研究的目標為「改進sorafenib治療肝癌的療效」。過去2年，我們已完成並發表成果如下: (1). 我們發現sorafenib與MEK抑制劑併用可以於多數的肝癌細胞與人類血管內皮細胞產生誘發凋亡的協同作用，主要的機制為抑制ERK的磷酸化與增加Bim (Clin Cancer Res 2009;15:5820-8）；(2). 我們發現併用sorafenib與bortezomib能克服肝癌細胞對於bortezomib的抗藥性，並且產生協同作用。主要的機制為恢復bortezomib對於PP2A的增強作用進而抑制的Akt磷酸化(J Hepatol 2010;52:88-95)；(3). 併用sorafenib與TRAIL 能改善肝癌細胞對於TRAIL的抗藥性，主要的作用機制為抑制Stat3的磷酸化進而抑制Stat3調控的影響細胞凋亡的蛋白質包括Mcl-1, Survivin, Cylcin D1。(Clin Cancer Res 2010; 16:5189-99 )；(4). 我們藉由將肝癌細胞暴露於低劑量sorafenib並逐漸增加劑量，我們以成功地建立多株sorafenib抗藥性的肝癌細胞株，我們發現PI3K/Akt訊息傳遞路徑的抗藥性的主要原因，因此我們合併MK-2206 (Merck, USA), an allosteric Akt inhibitor,與sorafenib來克服活化肝癌細胞株對於sorafenib抗藥性，達到更有效的抑癌效果。(J Pharmacol Exp Ther, Epub 2011 Jan 4)。未來一年，我們計劃執行三個新的研究主題，希望能發展更多方法來增強sorafenib治療肝癌的療效。第一部份，我們會研究CS-1008 (Daiichi-Sankyo, Japan)與sorafenib的併用。CS-1008為嶄新的TRAIL抗體，TRAIL抗體如CS-1008於人體的半衰期比TRAIL長許多，臨床上使用較便利。因此，我們要延續先前的研究工作，進一步探討CS-1008與sorafenib的併用效果。第二部份的研究，我們會探求併用放射治療與sorafenib的可行性。數十年來，放射治療雖已經有效使用於各種癌症的治療，但是對於肝癌病患治療效果不佳。對此，我們初步的結果發現放射治療與sorafenib併用於許多肝癌細胞株皆有更強的效果。因此，我們在未來一年中，將完成此一部份的研究並進行動物實驗，並尋求相關作用機制。第三部份的研究，我們將探求LCL-161(Norvatis, Switzerland), a pan IAP inhibitor, 與sorafenib的併用。我們初步的結果發現LCL-161與sorafenib併用於肝癌細胞株有更強的效果，在未來一年中，我們將完成此一部份的研究，並探討相關作用機制，希望我們的研究結果能成為未來臨床試驗的學理基礎。<br> Abstract: This project aims to improve the therapeutic efficacy of sorafenib.We have finished and published important results as follow: (1). Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. (Clin Cancer Res 2009;15:5820-8). (2). Combination of sorafenib and bortezomib shows synergy in HCC through PP2A-dependent Akt inactivation (J Hepatol 2010;52:88-95). (3). Sorafenib sensitizes resistant HCC cells to TRAIL-induced apoptosis at clinical achievable concentrations, and this effect is mediated via the inhibition of STAT3 (Clin Cancer Res 2010;16(21):5189-99). (4). Activation of PI3K/Akt signaling pathway medicates acquired resistance to sorafenib in HCC cells. The combination of sorafenib with MK-2206, an Akt inhibitor, overcomes the resistance. (J Pharmacol Exp Ther, Epub 2011 Jan 4).In the next year, we will explore more possibilities to enhance the effect of sorafenib in HCC.First, we will examine the combination of sorafenib and CS-1008, a novel TRAIL-receptor (DR5) agonist antibody, in HCC. TRAIL antibody like CS-1008 has much longer half-life in human than TRAIL and is more feasible in clinical use. Therefore, we would like to examine the combination of CS-1008 and sorafenib in HCC and explore the related mechanism.Our second aim is to examine the effect of radiotherapy and sorafenib in HCC. Radiation therapy has been used as a standard treatment of cancer for several decades. However, the treatment response of radiotherapy in HCC is not good. In this regard, our preliminary data showed that sorafenib enhanced radiation-induced apoptosis in HCC cells. Therefore, we will examine the in vivo effect and explore the related mechanism.Thirdly, we will focus on LCL-161, a pan-IAP inhibitor, in HCC. Our preliminary data indicated that combination of LCL-161 and sorafenib shows synergy in several HCC cell lines. Therefore, we will examine the effect of LCL-161 in combination with sorafenib in HCC.Hopefully, our work can find more useful information to improve the treatment response of sorafenib in HCC patients.