利用新型脂質體LPPC-Cetuximab吸附上shRNA表現基因後針對EGFR變異型肺癌進行標靶治療

Abstract

近年來的研究已發現表皮生長因子受器的抑制劑對於肺癌治療的成效因為抗藥性的產生而隨之減低，而後續發展出的第二代抑制劑仍會不斷地有新型抗藥機制的出現，因此本研究的策略即為找出在表皮生長因子受器變異型的肺癌細胞中會廣泛過度表現的潛力治療基因，並直接就基因層次的抑制來進行肺癌治療。我們利用生資系統性分析工具以及線上生物性資料庫Gene Expression Omnibus(GEO)，成功發展出一套篩選具治療潛力基因的系統平台。我們從GEO資料庫取得55株肺癌細胞株以及279肺癌臨床樣品的全基因圖譜，根據平台的篩選機制下我們找到了22個會在肺癌細胞廣泛過度表現的基因群，且發現他們都與細胞周期的調控相關。後續經由重要性排名與初步實驗，並利用已建立的標靶系統將shRNA送入表皮生長因子受器變異型之細胞株NCI-H1650，進一步驗證對腫瘤的治療效果。

Recent studies have revealed that EGFR inhibitors were no longer effective in the treatment of EGFR-activating lung cancer due to the development of resistance. Although the irreversible second-generation EGFR TKIs were clinically developed to overcome the resistances, there was still the emergence of other resistant mechanisms. Therefore, our strategy was to search for the potent therapeutic genes which were commonly over-expressed in EGFR-activating lung cancer and directly silenced the genes for tumor inhibition. With powerful analysis tools of bioinformatics and rich online published microarray datasets from Gene Expression Omnibus (GEO), we developed a screening system and to search for the best therapeutic targets of lung tumors. The total gene profiles of 55 lung cancer cell lines and 279 clinical lung cancer samples were obtained from online GEO datasets. Following the process of screening filters, we got the 22 candidate genes which were commonly over-expressed and all associated with cell cycle regulation. After ranking the importance and experimental verification, we finally chose the potent therapeutic gene for further lung cancer gene therapy. By using the well-established LPPC/cetuximab delivery system, we delivered the shRNA-expressed transgene into EGFR-mutant NCI-H1650 and verified its anti-cancer effects.