2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647505摘要：依據行政院衛生署在民國98 年公佈的資料顯示，惡性腫瘤仍是民眾年度死亡原因之首位，佔了28.1％，其中消化系統衍生之惡性腫瘤佔了前十大主要癌症一半以上的比例，因此如何選擇適當的病患接受有效但昂貴的分子標靶治療是一重要的公衛課題。雖然 Ras 致癌基因在四成左右的實質性腫瘤產生突變，也有證據顯示此種突變會削弱大腸癌病患接受上皮細胞生長因子接受器之標靶治療的效果，但是目前只能依賴傳統的核酸定序來找出有Ras 致癌基因的突變，由於Ras 與其相關的鳥糞嘌呤核甘三磷酸脢除了本身基因突變外還可以受到其他許多層次的調控，所以我們提出建立在腫瘤標本本身上可以鑑定Ras 活性的試劑，並藉由此新穎分析方式所得的結果去和病人接受標靶治療後的反應做比對，我們希望可以提供推廣此一分析方法到更多其他臨床檢體應用的佐證。有鑑於我們之前在大腸直腸癌病人觀察到 EBP50 在病灶細胞核不正常的表現與不良預後的關聯性，我們也建議在胃癌及胰臟癌病人檢體進行類似的分析，若是可以得到相同的研究結論，我們會利用表現綠色螢光蛋白標定的EBP50 之細胞株進行藥物篩檢，期待找出可以抑制EBP50 近入細胞核的藥物，而希冀此種藥物可以選擇性地抑制EBP50 入核引發癌化的機轉，但卻不妨礙EBP580 在其他細胞位置的功能，進而使採用此一機制而進展的腸胃道腫瘤得到控制。<br> Abstract: According to the data released by the Department of Health in 2009, malignancycontinues to be the top cause for the annual mortality. Malignant tumor accounts for28.1% of the top ten mortalities, and cancers originate from digestive system areresponsible for more than half of the mortalities caused by malignancy. It istherefore an important public health issue to identify patients who would most likelybenefit from expensive molecule targeted therapy.Although ras oncogenic mutation occurs in about 40% of solid cancers and it has beenrecognized that K-ras mutation would compromise the efficacy of EGFR targettherapy in colon cancer patients, the identification of ras mutation in colorectalpatients who would benefit from EGFR target therapy relies on traditional DNAsequencing. However, the activities of Ras and related small GTPases are subject tomany regulatory mechanisms in addition to the mutational activation of the genes perse. We propose to create specific probes for examining the in situ activity of Ras andrelated small GTPases on tumor sections. We would then correlate the results out ofthis assay with the clinical responses of the patient cohort and judge the rationale of amore generalized application of this assay in clinical samples.In a separate study, we would examine the effect of aberrant nuclear expression ofEBP50 on the clinical outcome of gastric and pancreatic cancer patients based uponour previous finding that aberrant EBP50 in the nucleus of colorectal cancer is relatedto a poor prognosis. Once confirming this finding is reproducible in gastric andpancreatic cancers, we would use EGFP-tagged EBP50 expressing cell line for drugscreening to identify potential chemical which would inhibit nuclear entry of EBP50.Hopefully, drugs which would prevent nuclear entry of EBP50 but not affect itslocalization and presumably its function in the other parts of the cells could helpcontrol progression of gastrointestinal malignancy.大腸癌colorectal cancer