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1 吉非替尼对分子靶向抗癌药物研究的贡献是什么? 倪云峰, 闫小龙, 李小飞 ( 第四军医大学唐都医院胸外科, 陕西西安 ) Contribution of gefitinib to the research on moleculartargeting antineoplastic agent NI Yun-Feng, YAN Xiao-Long, LI Xiao-Fei Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi an , Abstract The molecular-targeting antineoplastic agent is the hot topic today in tumor therapy field, which can improve life quality and prolong survival time of patients with tumor. Professor Adjei and his colleagues provided an excellent review which elaborated the reasonable application and looked forward to the future of molecular-targeting antineoplastic agent in various tumor therapies in CA Cancer J Clin in However, after scrutinizing the review, we found the gefitinib was not mentioned in this review. Gefitinib is a very important molecular-targeting antineoplastic agent in term of lung cancer therapy, and to some extent the research achievement of gefitinib offers a new direction for further research of other molecular-targeting antineoplastic agents in the future. Consequently, our arguments in the Letter we wrote were published in CA Cancer J Clin. Keywords lung cancer; gefitinib; molecular-targeting antineoplastic agent 摘要分子靶向抗癌药物是近年来肿瘤治疗的研究热点, 此类药物对于改善肿瘤患者的生存质量和延长生存时间有着重要意义 2009 年美国 Adjei 教授在临床医师肿瘤杂志 (CA Cancer J Clin) 上发表了一篇综述文章, 该文阐述了分子靶向抗癌药物在各种肿瘤治疗中的合理应用, 也展望了其在未来肿瘤治疗中的重要作用文章面面俱到, 条理清楚, 堪称经典然而精读此文, 我们发现该综述在肺癌分子靶向抗癌药物介绍中未提及吉非替尼, 忽视了吉非替尼在分子靶向药物研究中的重要性基于对于分子靶向药物的新认识, 我们撰写的 Letter 发表在 CA Cancer J Clin 上关键词肺癌 ; 吉非替尼 ; 分子靶向抗癌药物目前, 肺癌已成为各种癌症死亡的首要原因发病率和死亡率呈上升趋势吸烟已被证实为肺癌发病的主要因素 2008 年美国肺癌新发病例人, 由肺癌导致的相关死亡人数人, 分别占美国男性女性癌症死亡率的 31% 26% [1] 2009 年美国肺癌新发病例人, 人死于肺癌相关疾病 [2] 估计到 2030 年, 全球将有 830 万人死于吸烟相关性疾病, 其中肺癌占 3.1% [3] 在中国, 通讯作者 : 李小飞博士, 教授, 主任医师 Tel:(029) lxfchest@fmmu.edu.cn 作者简介 : 倪云峰博士, 讲师, 主治医师研究方向 : 肺癌癌基因 Tel:(029) niyunfng@fmmu.edu.cn 36

2 名作点评肺癌已代替肝癌成为我国首位恶性肿瘤死亡原因, 占全部恶性肿瘤死亡的 22.7% 目前我国肺癌发病率每年增长 26.9%, 预计到 2025 年, 我国肺癌患者将达到 100 万, 成为世界第一肺癌大国现阶段, 肺癌的治疗主要分为手术化疗放疗及分子靶向治疗早期肺癌首选手术治疗, 晚期肺癌是化疗的适应证, 放疗可以为不适宜手术的肺癌患者带来福音那么对于不能手术不能化疗及放疗的患者, 我们该采取怎样的治疗措施呢? 近年来, 分子靶向治疗在肿瘤临床治疗中的广泛运用, 为上述患者带来了希望肿瘤分子靶向治疗是利用分子靶向药物特异性, 以肿瘤组织或肿瘤细胞中所具有的特异性分子为靶点, 阻断该靶点的生物学功能, 从而达到抑制肿瘤生长甚至肿瘤消退的目的分子靶向药物分为单靶点和多靶点药物目前临床应有比较广泛的有针对表皮生长因子受体 (EGFR) 的单靶点药物吉非替尼厄洛替尼西妥昔单抗及曲妥珠单抗, 针对血管内皮生长因子 (VEGF) 的单靶点药物贝伐单抗, 还有多靶点药物范德他尼和索拉菲尼虽然分子靶向药物已在临床广泛推广, 但其仍处于初级阶段, 而且目前尚无肿瘤分子靶向治疗的相关临床指南 2009 年美国 Adjei 教授在临床医师肿瘤杂志 (CA Cancer J Clin) 上发表的一篇题为 Novel agents on the horizon for cancer therapy 的综述文章 [4] 该综述详细阐述了分子靶向药物在各种肿瘤治疗中的合理应用, 也展望了其在未来肿瘤治疗中的作用文章从细胞膜表面受体分子细胞内信号分子表观遗传异常蛋白动力学肿瘤血管形成及细胞微环境等多方面介绍了目前临床上广泛应用及关注的各种靶向药物文章面面俱到条理清楚堪称经典但是在认真研读完这篇综述后, 我们发现文中在肺癌分子靶向治疗药物的介绍中, 只提到了厄洛替尼西妥昔单抗, 而未提及吉非替尼这是为什么呢? 先让我们了解一下吉非替尼吉非替尼是阿斯利康公司生产的口服选择性 EGFR 酪氨酸激酶抑制剂它于 2003 年 5 月被美国 FDA 批准用于治疗化疗失败的晚期非小细胞肺癌但美国 FDA 同时谨慎地认为, 尽管肿瘤病灶大小的改变可以作为吉非替尼是否有效的一个判断标准, 但更重要的依据应该是服药后患者的寿命是否得以延长因此, 首次关于吉非替尼肺癌生存期研究的临床试验 (ISEL) 随即展开出乎意料的是,ISEL 的关键临床试验初步分析结果表明, 对于受试人群而言, 吉非替尼与安慰剂相比, 在总体生存期方面没有显著性差异 [5] 因此, 2004 年阿斯利康撤销了吉非替尼在欧盟的上市申请,2005 年美国 FDA 限制了吉非替尼的临床使用不过之后的研究为吉非替尼的临床应用带来了曙光 2008 年柳叶刀 (Lancet) 杂志上一篇关于吉非替尼的临床研究表明, 在特定的人群如女性不吸烟腺癌患者中, 吉非替尼能提高无进展生存期 [6] 那么为什么这些患者能够受益呢?2009 年新英格兰医学杂志 (N Engl J Med) 上一篇文章中对两千多名肺癌患者进行了 EGFR 突变分析, 发现 350 名具有 EGFR 突变的患者中女性占 69.7%, 不吸烟的占 66.6%, 腺癌占 80.9% [7] 肺癌患者中 EGFR 基因突变主要表现为 19 外显子缺失突变及 21 外显子点突变, 这些基因突变提示患者对吉非替尼敏感 2009 年 N Engl J Med 的另一项临床研究发现, 对于非吸烟或少量吸烟腺癌及东亚人种这些特定人群, 吉非替尼在提高生活质量提高生存率方面优于目前临床广泛使用的紫杉醇联合卡铂化疗方案 [8] 更令人惊喜的是, 分别来自于意大利 [9] [10] [11] 法国及日本的临床研究结果认为, 吉非替尼可用于特殊人群 EGFR 突变及细支气管肺泡癌的一线治疗基于上述临床试验结果, 吉非替尼于 2009 年 7 月 1 日在欧洲上市在我们科, 对于女性不吸烟及腺癌的患者, 在不能耐受化疗术后转移或化疗失败的情况下, 推荐使用吉非替尼治疗, 效果良好同时, 我们也对靶向这个词有了新的认识, 靶向不仅指的是针对肿瘤特异性分子, 更为重要的是还指使用靶向药物的特殊人群而吉非替尼在这方面的研究成果对于以后的分子靶向药物临床研究有重要的指导意义基于对分子靶向药物的新认识, 我们撰写了一篇 Letter, 提出肿瘤医师及研究者不应忽视吉非替尼在肺癌靶向治疗中的作用虽然西方人种的 EGFR 突变只有大约 10%, 但这 10% 的患者可以获益于吉非替尼的治疗再者, 我们强调人种性别基因等因素在未来肺癌靶向治疗中应得到更多重视, 力争做到分子靶向治疗的更加个体化在这一方面, 我们也不断摸索前进, 近期我们已开展了对肺癌患者的 EGFR 突变检测我们坚信, 通过对服用吉非替尼药物的患者进行严格筛选, 使得分子靶向药物能够真正做到有的放矢, 精确制导 37

3 参考文献 [1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008[J]. CA Cancer J Clin, 2008, 58(2): [2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009[J]. CA Cancer J Clin, 2009, 59(4): [3] Navada S, Lai P, Schwartz AG, et al. Temporal trends in small cell lung cancer: analysis of the national Surveillance Epidemiology and End Results (SEER) database [J]. J Clin Oncol, 2006, 24(18): 384. [4] Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy [J]. CA Cancer J Clin, 2009, 59(2): [5] Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) [J]. Lancet, 2005, 366(9496): [6] Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial [J]. Lancet, 2008, 372(9652): [7] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer [J]. N Engl J Med, 2009, 361(10): [8] Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma [J]. N Engl J Med, 2009, 361(10): [9] Crinò L, Cappuzzo F, Zatloukal P, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study [J]. J Clin Oncol, 2008, 26(26): [10] Cadranel J, Quoix E, Baudrin L, et al. IFCT-0401 Trial: a phase II study of gefitinib administered as firstline treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype [J]. J Thorac Oncol, 2009, 4(9): [11] Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations [J]. J Clin Oncol, 2006, 24(21): 附录 A 给编辑部的信摘自 CA Cancer J Clin, (2009 年 5 月 12 日 ) Gefitinib should not be ignored by oncologists and researchers Dear Editor, The article written by Drs. Ma and Adjei [1] has provided an excellent overview on "Novel Agents on the Horizon for Cancer Therapy." We benefited a great deal from the extensive content. This review also elucidated the success of target-based cancer agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. However, the authors avoided mentioning gefitinib, which had a winding pathway to success. This may lie in the fact that AstraZeneca informed the FDA that a large randomized study failed to demonstrate a survival advantage for gefitinib in the treatment of non-small cell lung cancer (NSCLC). At the same time, AstraZeneca also withdrew its application to market gefitinib in Europe shortly after this announcement in The study results in Asia were quite different. Treatment with gefitinib is most effective in women, patients who have never smoked, patients with pulmonary adenocarcinomas, and patients of Asian origin. In these populations, such treatment is associated with favorable rates of objective responses, progression-free survival, and overall survival [2-3]. These populations also have a relatively high incidence of somatic mutations in the region of the EGFR gene that encodes the tyrosine kinase domain [4]. NSCLC patients who had a base-pair deletion at exon 19 (del746_a750) or a point mutation at exon 21 (L858R), were highly responsive to gefitinib [5]. Lately, in the study by Mok et al [6], patients of East Asian origin with adenocarcinoma who had little or no exposure to tobacco smoke were treated with either gefitinib or standard double chemotherapy. The results showed 25 percent of patients on gefitinib 38

4 名作点评 had no cancer growth within 12 months, compared with 7 percent on chemotherapy. The median overall survival is slightly better with gefitinib than with chemotherapy. The presence of an EGFR mutation was a robust predictor of improved progression-free survival with gefitinib, as compared with carboplatin Cpaclitaxel, and of the benefit of gefitinib with respect to the objective response rate, indicating that patients in whom an EGFR mutation has been identified will benefit most from first-line therapy with gefitinib. The non-randomized European study by Rosell et al [7] shows the feasibility of large-scale screening for EGFR mutations in patients with advanced non-small cell lung cancer for selection for erlotinib therapy. Overall, the rate of survival of patients carrying an EGFR mutation who were treated with the tyrosine kinase inhibitor was relatively high, as compared with that of historical control subjects who were treated with chemotherapy. Accumulating studies show promising treatment effects with gefitinib on NSCLC patients with EGFR mutation recently. Those studies show us molecular analysis of EGFR and other pathways in the patient's tumor cells (including key mutations, copy-number changes of genes, and expression and activation of genes) may play a dominate role in individualized therapy of cancer. Based on those studies, the European Commission granted marketing authorization for oral gefitinib for locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor-tyrosine kinase (EGFR-TK) across all lines of therapy on July 1, Later, the American Society of Cinical Oncology updated the clinical practice guideline on chemotherapy for stage IV NSCLC. In the guideline, the first-line use of gefitinib may be recommended for patients with a known EGFR mutation. Either docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy [8]. The winding pathway of gefitinib sets us a very good example that detailed information, such as gender, ethnicity, confirmed habits, and molecular analysis, should be considered in targeted therapy, especially in this era when novel agents are on the horizon for cancer therapy. Yours Sincerely, Xiaolong Yan, M.D., Ph.D. (1) Jian Wang, M.D., Ph.D. (1) Yunfeng Ni, M.D. (1) Yongan Zhou, M.D., Ph.D. (1) Xiaofei Li, M.D., Ph.D. (1) Jing Han, M.D., Ph.D. (2) 1 Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi an City, Shaanxi Province, , 2 Department of Ophthalmology, Tangdu Hospital, Fourth Military Medical University, Xi an City, Shaanxi Province, , Correspondence to: Prof. Xiaofei Li (lxfchest@fmmu.edu.cn, Department of Thoracic Surgery,) or Jing Han(hanjing@fmmu.edu. cn, Department of Ophthalmology); Tangdu Hospital, Fourth Military Medical University, Xi an City, Shaanxi Province , References [1] Ma WW, Adjei AA. Novel agents on the horizon for cancer therapy. CA Cancer J Clin, 2009, 59: [2] Kim ES, Hirsch V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet, 2008, 372: [3] Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 2005, 366: [4] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med, 2009, 361: [5] Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med, 2004, 350: [6] Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361:

5 [7] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med, 2009, 361: [8] Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small cell lung cancer. Clin Oncol, 2009, 27: 名品精读溶酶体相关膜蛋白作为嵌合体可显著增强基于 SARS 冠状病毒核蛋白优势 T 细胞表位簇 DNA 疫苗的免疫应答杨琨, 孙凯,Srinivasan KN, 等 Gene Ther, 2009, 16(11): 由于常规 DNA 疫苗进入体内, 表达的目的蛋白属内源性抗原, 抗原提呈细胞 (antigen presenting cell, APC) 将启动 MHCI 类抗原加工途径, 提呈 MHCI/ 抗原肽复合物给 CD8 + T 细胞, 因此,CD4 + T 细胞不能被有效活化溶酶体是外源性抗原加工途径 MHCII 类分子器室 (MHC class-ii compartment,miic) 的重要组成部分溶酶体相关膜蛋白 (lysosome associated membrane protein,lamp) 通过其胞浆尾的靶向作用, 与内吞体 / 溶酶体 (endosome/lysosome) 结合并翻转进入其中, 可将插入 LAMP 分子 luminal domain 和 transmembrane/cytoplasmic tail 基因之间目的基因编码的抗原直接携带进入 MIIC, 从而实现 DNA 疫苗所表达蛋白从内源性抗原的 MHCI 类加工途径向外源性抗原的 MHCII 类加工途径的转化我们实验室 Gupta 等通过软件预测了 SARS 冠状病毒核蛋白 (SARS CoV-N) 的优势 T 细胞表位, 并对 SARS CoV-N 的两种不同形式所免疫 BALB/c 鼠的 IFN-γ 应答谱进行了分析, 发现在 SARS CoV-N 的 N 端 aa 存在 T 细胞优势表位簇在此基础上, 本文构建了 4 种不同形式的重组质粒 :p-n( 含可编码全长 SARS CoV-N 基因 );p-lamp/n( 含可编码全长 SARS CoV-N 基因与 LAMP 基因的嵌合体 );p-n70-122( 含可编码 SARS CoV-N 优势 T 细胞表位簇基因 );p-lamp/n70-122( 含可编码 SARS CoV-N 优势 T 细胞表位簇基因与 LAMP 基因的嵌合体 ) 分别用这 4 种重组质粒和对照载体质粒 (p-lamp/den-env,den-env 为编码登革热病毒囊膜蛋白基因 ) 尾根部皮下免疫 BALB/c 小鼠连续免疫 3 次, 每次间隔 3 周, 每次每只鼠 50 μg 质粒第 3 次免疫后 24 周, 加强免疫 1 次通过间接 ELISA 检测抗体产生水平 ELISpot 检测细胞因子分泌水平, 对这 4 种不同质粒免疫小鼠后所诱导的免疫应答进行评估结果显示, 首次免疫后,p-LAMP/N 就可诱导较强的抗体应答 ; 两次免疫后,p-LAMP/N 和 p-n 均可诱导很强的抗体应答 ; 而 p-lamp/n 则需要 3 次免疫, 才可诱导较强的抗体产生 ; 对照组及 p-n 组没有观察到明显的抗体产生选用覆盖 SARS CoV-N 全长或优势 T 细胞表位簇的重叠肽 (15-mer,overlapping 10aa) 行 ELISpot 检测各组免疫脾细胞特异性分泌 IFN-γ IL-2 IL-4 及 IL-10 细胞因子水平发现,p-N 可诱导产生一定水平的 IFN-γ, 但 p-lamp/n 和 p-lamp/n 组则是 p-n 组的 2 倍, 而对照组及 p-n 组没有观察到明显的 IFN-γ 分泌 ;p-lamp/n 和 p-lamp/n 均可诱导高水平 IL-2 IL-4 及一定水平 IL-10 分泌 (P >0.05), p-n p-n 和对照组则没有观察到明显的上述细胞因子分泌第 3 次免疫后 24 周, 加强免疫前后 ELISpot 检测 IFN-γ 发现, 无需加强免疫,p-LAMP/N 和 p-lamp/n 均可诱导一定水平 IFN-γ 产生, 而 p-n p-n 和对照组则检测不到 IFN-γ 的产生 ; 加强免疫后,p-N 可诱导一定水平 IFN-γ 分泌,p-LAMP/N 和 p-lamp/n 诱导 IFN-γ 分泌水平则显著升高 (P <0.01), 对照组及 p-n 组仍没有观察到明显的 IFN-γ 产生上述结果表明 :LAMP 不仅可明显提高病原体全长蛋白成分 DNA 疫苗的免疫效率, 而且即使基于优势表位的 DNA 疫苗, 也因与其构成嵌合体, 能够诱导机体产生很强的特异性免疫应答及维持长效免疫记忆 40

何秋琳张立春视觉学习研究进展视觉注意视觉感知

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