基因表达谱大数据在抗癌药物研发中的应用

doi:10.11959/j.issn.2096-0271.2016051

摘要/Abstract

摘要：

作为功能基因组学中重要的组成部分，基因表达谱在生物学、医学和药物研发等多个领域发挥着重要作用。特别是随着精准医疗概念的提出，整合包括基因表达谱在内的多组学数据用于个性化医疗是未来的发展趋势。从抗癌药物研发背景出发，介绍了基于细胞扰动表达谱的大数据分析方法，并且总结了其在抗癌药物研发中的应用。

关键词: 基因表达谱, 关联图谱, 整合网络细胞印记库, 抗癌药物研发

Abstract:

As an important part of functional genomics,gene expression profile plays an important role in many fields,such as biology,medicine and drug discovery.With the advent of precision medicine,integration of multi-omics data including gene expression profile data for personalized health care is becoming the trend of future medicine.The advances of anticancer drug development were introduced firstly,and then the methods for perturbational gene expression profile analysis were illustrated,especially connectivity map idea.Finally applications of these data in anticancer drug development were summarized.

Key words: gene expression profile, connectivity map, library of integrated network-based cellular signatures, anticancer drug development

刘阳, 白卉, 伯晓晨. 基因表达谱大数据在抗癌药物研发中的应用[J]. 大数据, 2016, 2(5): 22-31.

Yang LIU, Hui BAI, Xiaochen BO. Application of large scale gene expression profiles in anticancer drug development[J]. Big Data Research, 2016, 2(5): 22-31.

图/表 2

图1

表1

CMap与LINCS用于抗癌药物研发研究汇总（2012年至今）"

疾病	药物	主要发现	参考文献
肝癌	Cisplatin（顺铂），Sorafenib （索拉非尼），5-fluorouracil （5-氟尿嘧啶）	3种药物增加组蛋白乙酰化，将生存率低的病人的表达谱逆转到生存率高的病人的表达谱	[27]
胶质母细胞瘤	Pyrvinium（扑蛲灵）	靶向CD133（肿瘤干细胞标志物），体内外实验证实其抑制胶质母细胞瘤自我更新和增殖	[28]
结直肠癌	Chlorpromazine（氯丙嗪）	抗精神病药物氯丙嗪可以抑制p53（一种抑癌基因，在癌症中高突变）突变结肠癌细胞系生长，促进其凋亡，SIRT1（蛋白去乙酰化酶，在基因调控、代谢、癌症等方面发挥重要作用）	[29]
急性淋巴细胞白血病	类视黄醇	类视黄醇诱导IKZF1（编码具有锌指结构的转录因子蛋白，在淋巴细胞分化和发育中起调控作用）表达，抑制BCR-ABL1型急性淋巴白血病细胞增殖，同时可以增强达沙替尼药效	[30]
结直肠癌	Irinotecan（伊立替康）和Etoposide（依托泊苷）等10多种药物	采用多个结肠癌数据集构建表达谱印记，筛选出10多种药物与表达谱印记关联，包括已知的化疗药物	[31]
髓母细胞瘤	Alsterpaullone	Alsterpaullone抑制细胞周期相关基因，下调MYC基因（一种癌基因），提高3型髓母细胞瘤生存率	[32]
急性淋巴细胞白血病	SB225002	SB225002通过激活GLIPR1（神经胶质瘤发病相关蛋白），诱导B型和T型急性淋巴细胞白血病细胞周期停滞和细胞凋亡	[33]
弥漫性大B细胞淋巴瘤	Doxycycline（多西环素）	抗生素多西环素可以影响多个淋巴瘤形成信号通路，抑制肿瘤细胞生长，CSN5为其潜在药靶	[34]
肺腺癌	Bezafibrate（苯扎贝特）	苯扎贝特通过靶向CDK2（细胞周期蛋白激酶），抑制肺腺癌细胞生长	[35]
肺腺癌	Valproic acid（丙戊酸）	与厄洛替尼联用可以引起酪氨酸激酶抑制剂耐药性肺腺癌细胞凋亡，可能作用于MAPK（促分裂原活化蛋白激酶）与AKT（一种丝/苏氨酸蛋白激酶）信号通路	[36]
肺癌	Forskolin（佛司可林）与6种PGE-2类似物	CRTC1激活剂与LKB1缺失的肺癌相关，COX-2抑制剂可以抑制LKB1缺失的肺腺癌细胞生长	[37]
结直肠癌	Citalopram（西酞普兰）， Troglitazone（曲格列酮）， Enilconazole（恩康唑）	抗抑郁药西酞普兰，抗糖尿病药曲格列酮，杀真菌剂恩康唑通过抑制TGFβ（一种转化生长因子）通路，可以抑制结肠癌细胞生长，西酞普兰可以进一步抑制转移结肠癌细胞生长	[38]
非小细胞肺癌	Bosutinib（博舒替尼）	博舒替尼可以抑制对酪氨酸酶抑制剂具有耐药性的非小细胞肺癌（EGFR（表皮生长因子受体）突变）细胞增殖，引起凋亡，与吉非替尼具有协同效果	[39]
肾细胞癌	Pentamidine（喷他脒）	前期临床试验喷他脒可以延缓肾细胞癌生长	[40]
小细胞肺癌	Rapamycin（雷帕霉素）	雷帕霉素可增强ABT-737药效，用于治疗小细胞肺癌	[41]
卵巢癌	17-AAG	17-AAG抑制DNA的同源重组修复，可提高卵巢癌患者对PARP （DNA修复酶，在DNA损伤修复和细胞凋亡中发挥重要作用）抑制剂奥拉帕尼和卡铂的敏感性	[42]
结直肠癌	Phenoxybenzamine（酚苄明），GW-8510，Imipenem （亚胺培南）	FMCM用于药物重定位，并且发现3个药物具有治疗结肠癌的作用	[43]
非小细胞肺癌	多种小分子药物	药物重定位分析挖掘早晚期非小细胞肺癌的治疗药物	[44]
急性髓性白血病	Tipifarnib	法尼基转移酶抑制剂Tipifarnib可抑制Rheb的异戊烯化并稳定Bax	[45]
胰腺癌	Tomatidine（番茄碱）， Nialamide（尼亚酰胺）	Tk1（胸苷激酶，是癌变细胞DNA合成必需的前体物）可能与胰腺癌发展相关，番茄碱和抗抑郁药尼亚酰胺可作为治疗胰腺癌的候选药物	[46]
急性髓性白血病	Entinostat（恩替诺特）	HDAC（组蛋白去乙酰化酶，对染色体的结构修饰和基因表达调控发挥着重要的作用）抑制剂恩替诺特延长白血病小鼠模型的存活期	[47]
肝癌	黄连素	黄连素引起肝癌细胞系细胞周期停滞，并且可能与调钙蛋白有关	[48]

表1

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