2017-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659354摘要：非小細胞肺癌 (NSCLC) 常在癌症晚期才被診斷，預後不良致死率高。化療藥物如cisplatin是NSCLC主要之治療方式，但副作用大。上皮生長因子受體 (EGFR) 是一種受體酪氨酸磷酸酶，可促進細胞生長、增生及存活，EGFR單株抗體和EGFR酪氨酸磷酸酶抑制劑 (TKI) 對頭頸癌、大腸直腸癌和NSCLC有良好之治療效果，顯示EGFR為癌症治療之標靶；降低EGFR之表現亦為俱潛力之治癌策略。EGFR TKI僅對EGFR突變之NSCLC病患具療效，此類病人東方佔50%，西方佔10%，因此，仍需研發其他種類NSCLC之治療，例如去乙醯酶抑制劑 (HDACi)。C-Cbl蛋白為一種E3 ligase，許多血液腫瘤中發現c-Cbl之突變，表示其腫瘤抑制之功能。我們的初步結果顯示，肺癌病患之檢體不表現c-Cbl蛋白，在NSCLC細胞株transfect c-Cbl可抑制其增生、促進PARP及pro-caspase 3分解及降低EGFR之表現，我們篩選一系列小分子化合物，發現HDAC抑制劑SAHA可以促進c-Cbl之表現，進一步合成比SAHA效用更強之新穎HDAC抑制劑WJ，WJ於NSCLC細胞株亦可促進c-Cbl之表現；根據這些初步結果，未來三年將執行三項目標：(一) 探討阻斷EGFR對各NSCLC細胞株生長之影響，及WJ在各NSCLC細胞株是否均誘導c-Cbl之表現 (二) 探討WJ抑制腫瘤生長及促進凋亡作用是否與其誘導c-Cbl相關，並探討其分子機制 (三) 探討WJ與cisplatin或paclitaxel合併使用之抗癌效果。此研究將揭露HDAC抑制劑於非小細胞肺癌之治療及其新穎抗癌機轉。<br> Abstract: Non-small cell lung cancer (NSCLC) is a worldwide cancer usually diagnosed at advanced stage with poor outcome. Chemotherapy like cisplatin remains the mainstay for NSCLC, but toxicities hinder its application. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that promotes cellular growth, proliferation, and survival. Clinically, anti-EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor (TKI) have led to great success in head and neck cancer, colorectal cancer, and NSCLC, suggesting that targeting EGFR is an important strategy for cancer treatment. In addition, down-regulation of EGFR can also be a potential strategy for cancer treatment. EGFR TKI only benefits to a subgroup of NSCLC patients with EGFR activating mutation. Thus, new treatment like novel HDAC inhibitor (HDACi) is sought to treat NSCLC without EGFR activating mutations or those with acquired resistance to EGFR TKI. Casitas B-lineage lymphoma (c-Cbl) protein is an E3 ubiquitin ligase regulating intracellular signaling. Its mutation has been reported to induce myeloid neoplasm while overexpression inhibits tumor growth, implicating its tumor suppressive role. Our preliminary data demonstrated the loss of c-Cbl expression in lung cancer patient specimens. Overexpression of c-Cbl in NSCLC cells inhibited cell proliferation and induced PARP and pro-caspase 3 cleavages as well as down-regulated EGFR expression. We screened a series of small molecules and found that HDACi SAHA could induce c-Cbl expression. A novel HDACi, WJ more potent than SAHA is synthesized. WJ induced c-Cbl expression in NSCLC cells. Three specific aims are therefore proposed to be executed within three years: (1) To examine the effect of EGFR knockdown on cell viability and whether WJ induces c-Cbl in various NSCLC cells. (2) To study whether WJ-induced growth inhibition and apoptosis in vitro and in vivo are related to c-Cbl induction and the underlying mechanism. (3) To investigate the anti-cancer effect of combination of WJ with cisplatin or paclitaxel. This study will reveal the novel anticancer mechanism of HDAC inhibitors for the treatment of NSCLC.