2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643673摘要：非小細胞肺癌(NSCLC)常會表現過量之上皮生長因子受體(EGFR)，促成癌細胞快速生長與轉移。Tyrosine Kinase inhibitor (TKI)，如gefitinib與erlotinib，能抑制過度活化之EGFR，使癌細胞無法增長與轉移，進而達到治療NSCLC之效果。然而， TKI之治療會產生抗藥性而導致治療失敗。TKI抗藥性之產生，係EGFR產生二次突變，如Threonine 790 突變為Methionine，或其他gene之變異例如c-MET之大量表現。因此，若針對突變之EGFR以及c-MET設計出新的治療方式，應可有效克服NSCLC對TKI之抗藥性。組織蛋白去乙醯酶 (Histone deacetylase, HDAC)會移除染色質組織蛋白之乙醯基，使染色質呈現緊緻的狀態，因而抑制基因之表現。腫瘤細胞中會過度表現HDAC，因而降低抑癌基因(tumor suppressor gene)之表現，因此，HDAC為新興癌症治療之熱門標的，多種小分子 HDAC 抑制劑將發展為治癌藥物，其中SAHA (Vorinostat)已被FDA核准用於治療皮膚T 細胞淋巴癌。我們發展了一系列新穎的HDAC抑制劑 (WJ compounds)，經測試後發現WJ compounds對HDAC之抑制效果勝於SAHA。初步的結果顯示，WJ compounds與Gefitinib合併使用，能加乘地抑制gefitinib抗藥性細胞之生長； WJ compounds能同時降低NSCLC細胞EGFR與c-MET的表現，此效果亦大於SAHA。因此WJ compounds可同時抑制HDAC，EGFR以及c-MET，如能進一步研究與最適化，相信能用於克服TKI之抗藥性，並造福NSCLC之病患。本三年期計畫第一年將評估WJ compounds與gefitinib合併使用於NSCLC之效果，並探討WJ compounds是否能克服gefitinib之抗藥性；同時將對WJ compounds做結構性的修飾，以增加其療效與專一性。第二年將利用臨床前小動物實驗模式評估，WJ compounds與gefitinib併用之安全性，以及對gefitinib有抗藥性NSCLC之治療效果。第三年將深入探討WJ compounds影響EGFR以及c-MET表現之分子機轉。<br> Abstract: Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first identified in 2004 as a distinct molecular subset of lung cancer. Although tyrosine kinase inhibitors (TKIs) are useful for the treatment of these patients, primary and acquired resistance to these agents are inevitable and remains a major clinical issue. Secondary mutations in EGFR like T790M and/or amplification of the gene encoding the c-MET receptor tyrosine kinase make up most cases of resistance. Accordingly, targeting mutant EGFR and c-MET is presumably a useful approach to overcome TKI resistance in NSCLC. Histone deacetylases (HDACs) are histone-modifying enzymes that remove the acetyl group from core histones or other proteins such as transcription factors, and have a key role in the regulation of gene expression. Inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to induce growth arrest, differentiation, and apoptotic cell death of tumor cells. We have developed a series of novel HDACi, WJ compounds, which are much more potent than SAHA (Vorinostat, the only HDACi approved by FDA). Our preliminary data showed that combination of WJ compounds with gefitinib (Iressa) synergistically inhibits the growth of TKI-insensitive or -resistant NSCLC cells. Moreover, WJ compounds reduced EGFR and c-MET expression concomitantly in lung cancer cells, implying that WJ compounds may be an ideal approach to overcome the TKI-resistance in NSCLC. Overall, WJ compound is much better than SAHA in many ways including inhibition of HDAC, EGFR, and c-MET. Advanced investigation and further optimization of WJ compounds are presumable to create greater therapeutic benefits in NSCLC.Based on our preliminary results, we propose three specific aims to be executed in three years: (1) Effect of WJ compounds on gefitinib-resistant NSCLC cell lines and optimization of lead WJ compounds to improve their potency. (2) Combination of WJ compounds and gefitinib for the treatment of lung cancer in preclinical animal study. (3) Investigation of the molecular mechanism of WJ compounds to inhibit EGFR and c-MET expression. This project will focus on the clinical development of WJ compounds as novel, highly selective HDAC inhibitors and offer the opportunity to rapidly bring to market as an innovative, best-in-class treatments for NSCLC cancer patients, especially who develop acquired resistance to EGFR-TKI therapy.gefitinib抗藥性HDAC非小細胞肺癌gefitinib resistanceHDACNSCLC