2010-01-012024-05-15https://scholars.lib.ntu.edu.tw/handle/123456789/663206摘要：肺癌是世界上造成癌症死亡的頭號殺手，每年約造成130 萬人死亡。其五年的總存活率只有15%，而且近幾十年來並沒有改善的跡象。即便是手術治療、放射線療法及化療，病人預後仍相當差，所以找到新的抗肺癌藥物是迫切需要的。系統生物學是生物學中一個新興的研究領域，著重於以系統的觀點來了解生物體的運作。近年來高通量藥物合成、蛋白質體、微陣列及生物資訊技術的發展，促使系統生物學能加快闡明生化路徑、藥物開發與應用於疾病治療的速度。 癌組織標靶治療是加速抗癌治療最有效的方法之一，尋找有效的標靶—例如在不正常的特定區域中大量表現的蛋白質—在癌症治療上是重要的研究主題。先前我們利用系統生物學方法找到新一類的抗癌化合物—ATP 合成&#37238;抑制劑，可做為治療乳癌的標靶藥物，這項研究成果發表在2008 年的Journal of Proteome Research 期刊，並獲選為美國化學會及科學今日的熱門新聞，特別報導我們「首次發現阻斷能量供應蛋白質能殺死癌細胞」。除了乳癌之外，我們最近的初步研究發現，ATP 合成&#37238;也會在肺癌病人的癌化組織中高度表現；以ATP 合成&#37238;抑制劑處理肺癌細胞進行實驗，觀察到肺癌細胞會遭受毒殺，但對正常細胞給予相同劑量時卻無影響。 本計畫主要的目標是利用系統生物學研究法找到抗肺癌藥物並研究以ATP合成&#37238;抑制劑為主的標靶治療及其作用的分子機制。 本計畫特定的目標如下： 1. 研究肺癌組織及細胞株上ATP 合成&#37238;的表現量。 2. 測量在肺癌細胞表面ATP 合成&#37238;的活性。 3. 測量ATP 合成&#37238;抑制劑在癌化的抑制效果及探討何種細胞死亡會發生。 4. 發展動物模式實驗來研究ATP 合成&#37238;抑制劑在活體內抗腫瘤生長及轉移的情形。 5. 研究ATP 合成&#37238;抑制劑所調控的癌細胞生長抑制及死亡的分子作用機制。 本計畫相當符合基因體醫學國家型計畫的目標，著重於發展肺癌的標靶治療，藉由探討ATP合成&#37238;抑制劑作用於肺癌細胞的分子機制，開發出有潛力的抗肺癌藥物。<br> Abstract: Lung cancer is the most common cause of cancer death in the world and causes 1.3 million deaths per year worldwide. The five-year, overall survival rate is 15% and has not been improved over many decades. Even with improving efficacy of surgical treatment, radiation therapy, and chemotherapy, prognosis for lung cancer patients is still poor. Identification and discovery of novel drugs for lung cancer therapy is therefore imperative. Systems biology is a new field in biology that focuses on understanding functional activities from a system-wide perspective. With the advent of high-throughput drug synthesis, proteomics, transcriptomics and bioinformatics technologies, systems biology has become a viable approach to improve our knowledge of health and disease. This holistic approach will enable more rapid advances in elucidating biomolecular pathways and identifying targets for drug discovery and disease therapies. Targeting tumor tissues is one of the most powerful approaches to accelerate the efficiency of anticancer treatments. The investigation of effective targets, including proteins specifically and abundantly expressed in abnormal regions, has been one of the most important research topics in cancer therapy. Recently, we have applied systems biology approach on drug discovery for breast cancer and the results suggest that ATP synthase inhibitors may represent a new approach for fighting breast cancer and other cancers. The finding has been published in Journal of Proteome Research (2008) and was selected as a press release entitled “First evidence that blocking key energy protein kills cancer cells” by American Chemical Society and also reported in Science Daily News. Besides breast cancer, we also observed that ATP synthase was up-regulated in lung tumor tissues. In our preliminary studies, we treated the lung cancer cells with an ATP synthase inhibitor, Aurovertin B, and observed strong inhibition on the proliferation of several lung cancer cell lines but little influence on the normal cell line IMR-90. The broad and long-term objectives of this proposal are to apply systems biology for anti-lung cancer drug discovery and to study the targeting therapy by ATP synthase inhibitors and their related molecular mechanism. Specific Aims: 1. To investigate the ATP synthase expression level in lung cancer tissue and cell lines. 2. To measure the activity of ATP synthase on human lung cancer cell surface. 3. To measure the inhibitory effects on tumor metastasis and to examine which type of cell death is induced by ATP synthase inhibitors in cancer cells. 4. To develop animal models to examine anti-tumor growth and anti-tumor metastasis by ATP synthase inhibitor in vivo. 5. To elucidate the underlying molecular mechanism of ATP synthase inhibitor-mediated cancer cell inhibition and, ultimately, cell death. This proposal meets the aims put forward by the National Research Program for Genomics Medicine as it will focus on developing target therapies for lung cancer and elucidating the molecular mechanisms of ATP synthase inhibitor, a potential novel anticancer drug.肺癌ATP 合成&#37238ATP 合成&#37238抑制劑系統生物學蛋白質體學微陣列基因網路Lung cancerATP synthaseATP synthase inhibitorsystems biologyproteomicsmicroarraygene network