- 學位論文
胃癌之分子標靶治療– 著重於上皮生長因子接受器抗體(Cetuximab) 併用化學治療,及其相關藥物基因體學之研究
Molecular Targeted Therapy for Gastric Cancer ---with emphasis on EGFR antibody (Cetuximab) plus chemotherapy, and related pharmacogenomics
摘要
胃癌在東亞的發生率仍遠高於其他地區，所以胃癌的治療方針值得深入研究。目前胃癌的標準治療多採5-FU與platinum analogs雙方療法，不過治療的效果已達某一極限，為了增加胃癌的療效，所以新的治療方式則是併用分子標靶藥物。Cetuximab是針對許多腫瘤高度表現分子EGFR而研發，2004年經美國FDA通過可用於大腸癌的治療。由於胃癌也多有EGFR的表現，所以cetuximab也可能對胃癌的治療有所幫助。經由35位胃癌病人的cetuximab併用cisplatin與5-FU的第二期前瞻性臨床試驗，得到令人鼓舞的效果，治療效果可提高至68.6%，而中位存活期可達14.5個月。由於cetuximab藥物費用高昂，「個人化」的標靶治療更形重要。藉由藥物基因體學的研究，以期找到可能預測有效治療的基因特性。 本研究先利用細胞株群組來分析，發現EGFR 在codon521處有氨基酸變異，而且cetuximab對這些細胞有不同的生長抑制效果。10株codon521有arginine( R )的細胞株，7株會受cetuximab抑制，然而1株codon521為lysine( K )者，則生長不受抑制。進一步研究顯示521R的細胞株有化療增敏現象，而521K則沒有。分析細胞株的KRAS、BRAF、PIK3CA、Cyclin D1等已知基因，並未發現對cetuximab的生長抑制，會有顯著不同基因型的差異。 對於接受5-FU、cisplatin和cetuximab複方治療臨床試驗的35位胃癌病人，也進行與複方治療相關因子基因的研究。本研究分析了與5-FU療效有關的基因 Thymidylate synthase (TS)，已知TS基因之5端未轉譯區域(5’-UTR)之28個核苷酸三重複(3R)序列的TS表現比二重複(2R)序列顯著較高，本研究發現有腫瘤反應者22人中11人為3R type，而無腫瘤反應者11人中即有9人為3R type，由此推論3R type對此複方療法有較具抗性的趨勢。另外本研究也分析與cisplatin療效有關的基因ERCC1，可見ERCC1的表現量低者對此複方療法較具感受性( P=0.038)。至於與cetuximab療效可能相關的因子，本研究分析了EGFR521的基因型與KRAS、BRAF的突變，初步結果顯示EGFR521的基因型與複方療法的療效關聯性，但在現有樣本數分析未達顯著意義；而KRAS與BRAF的突變，在胃癌中發生率很低，且對療效的影響很有限。基於多重因子會影響複方療效，本研究也發展一項反應率貢獻加權分數，發現總分等於或低於0.48者，則82.3%可達治療效果，未來可能作為胃癌個人化治療的可行策略。
並列摘要
The incidence of gastric cancer is high in East Asia, so the study for the therapeutic regimens is important. At present, the combination of 5-FU and platinum analogs is still the well accepted standard regimen. The therapeutic effect had reached a plateau, so several molecular targeted agents are under evaluation in combination with chemotherapy. Cetuximab has been developed for targeting EGFR and approved for the treatment of metastatic colorectal cancer since 2004. Because EGFR is expressed in 50-60% gastric cancer, cetuximab may be effective in gastric cancer. Total 35 gastric cancer patients were recruited in the trial. The treatment results were promising, the response rate reached 68.6%, and the median survival reached 14.5 months. Cetuximab is expensive, so the personalized medicine by pharmarcogenomics is important. We analyzed several gastric and colon cell lines and found a SNP in EGFR codon521. This SNP leads an amino acid change from arginine( R ) to lysine( K ), and different types of EGFR521 had different sensitivity to cetuximab. Among 10 of R types,7 were growth inhibition by cetuximab, but the K type was not. Also the R types were more sensitive to the combination of chemotherapeutic agent and cetuximab than chemo- therapeutic agent alone. KRAS、BRAF、PIK3CA and Cyclin D1 were also analyzed; However, there was no correlation with growth inhibition by cetuximab. This study also analyzed several genes of the 35 gastric cancer patients recruited in the 5FU-cisplatin-cetuximab clinical trial. First, TS gene which is related to the resistance of 5-FU was analyzed. 11 of 22 responders were 3R type of 5’-UTR of 28 bps tandem triple repeats (i.e. high TS mRNA levels), and 9 of 11 non-responders were 3R type. It seems patients with 3R type of TS had less tumor response to the triplet therapy. Second, ERCC1 is a predictor of cisplatin response, and patients’ tumor tissues were analyzed for ERCC1 mRNA level. Patients with lower ERCC1 expression were more susceptible to the therapy (P=0.038). Finally, the EGFR521 was also determined, and seemed not related to the response with current sample size. The incidence of KRAS and BRAF mutation in gastric cancer was very low; the influence of those mutations to the response was not significant. A response rate-weighted score was developed and worthy for future study, with a predictive value (82.3% patients were responders among score equal or less than 0.48) was found.
參考文獻
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