[发明专利]抑制恶性肿瘤并增强化药疗效的活性肽及其应用

说明书

本发明公开了一种抑制恶性肿瘤并增强化药疗效的活性肽及其应用。该活性肽包括如下序列：Asn‑Val‑Phe‑Thr‑Val‑Ser‑Pro，可应用特异性抑制成纤维细胞生长因子刺激的细胞增殖、迁移和侵袭，以及血管生成，增强化药疗效，从而可用于治疗成纤维细胞生长因子及其受体介导的信号通路异常活化的多种恶性肿瘤，包括但不限于胃癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、肺癌、食管癌或结直肠癌等。本发明还公开了包含该肽的抗肿瘤药物和制备方法等。

技术领域

本发明属于肽技术领域，特别涉及一种抑制恶性肿瘤并增强化药疗效的活性肽及其应用。

背景技术

维持机体组织的内稳态依赖复杂的生长因子信号网络的调控，成纤维细胞生长因子(FGFs)及其受体(FGFR1-4)组成的信号网络在调控细胞与细胞之间相互作用中发挥着重要作用。根据序列同源性及系统发生的差异，可将已发现的包括18个成员的哺乳动物成纤维细胞生长因子家族(FGFs，包括FGF1-FGF10和FGF16-FGF23)分为6个亚家族：FGF1和FGF2；FGF3、FGF7、FGF10和FGF22；FGF4、FGF5和FGF6；FGF8、FGF17和FGF18；FGF9、FGF16和FGF20；FGF19、FGF21和FGF23。前期研究已明确前5个亚家族的成员属于自分泌/旁分泌配体，它们通过调节细胞的增殖、存活、迁移和分化，调控机体一系列的生物学功能，包括脑的发育、肢体的分化、躯干的形成和肿瘤的发生发展等。最后1个由FGF19、FGF21和FGF23组成的亚家族具有依赖于Klotho蛋白的内分泌调节作用，调控胆汁酸、胆固醇、葡萄糖、维生素D和磷酸盐的体内稳态。成纤维细胞生长因子家族成员通过与细胞表面受体FGFR结合，引起FGFR二聚化，使FGFR的胞浆近膜区和胞内的两个酪氨酸激酶区(TK1和TK2)相互接近而自身磷酸化，激活胞内信号转导通路，介导细胞增殖、迁移和侵袭等生物学活性。

FGFs在体内分布广泛且具有多种重要的生物学功能，其时空表达及表达水平受到严谨的调控。研究表明，属于自分泌/旁分泌配体的FGFs家族成员及其相应受体表达的异常上调与多种肿瘤的恶性进展和化疗敏感性密切相关(参见Brooks AN,Kilgour E,SmithPD.Molecular pathways:fibroblast growth factor signaling:a new therapeuticopportunity in cancer.Clin Cancer Res,2012,18(7):1855-1862；Sun C,Fukui H,HaraK,et al.FGF9from cancer-associated fibroblasts is a possible mediator ofinvasion and anti-apoptosis of gastric cancer cells.BMC cancer,2015,15:333；Huang Y,Jin C,Hamana T,et al.Overexpression of FGF9in prostate epithelialcells augments reactive stroma formation and promotes prostate cancerprogression.International journal of biological sciences,2015,11(8):948-960；Hendrix ND,Wu R,Kuick R,et al.Fibroblast growth factor 9has oncogenicactivity and is a downstream target of Wnt signaling in ovarian endometrioidadenocarcinomas.Cancer research,2006,66(3):1354-1362；Mizukami T,Togashi Y,Naruki S,et al.Significance of FGF9gene in resistance to anti-EGFR therapiestargeting colorectal cancer:Asubset of colorectal cancer patients withFGF9upregulation may be resistant to anti-EGFR therapies.Molecularcarcinogenesis,2017,56(1):106-117；Basu M,Mukhopadhyay S,Chatterjee U,etal.FGF16promotes invasive behavior of SKOV-3ovarian cancer cells throughactivation of mitogen-activated protein kinase(MAPK)signaling pathway.J BiolChem.2014,289(3):1415-1428；Chamorro MN,Schwartz DR,Vonica A,et al.FGF-20andDKK1are transcriptional targets of beta-catenin and FGF-20is implicated incancer and development.EMBO J.2005,24(1):73-84；Jeffers M,Shimkets R,PrayagaS,et al.Identification of a novel human fibroblast growth factor andcharacterization of its role in oncogenesis.Cancer Res.2001,61(7):3131-3138；Facchiano A,Russo K,Facchiano AM,et al.Identification of a novel domain offibroblast growth factor 2controlling its angiogenic properties.J BiolChem.2003,278(10):8751–8760；Yang ZL,Cheng K,Han ZD.Effect of bFGF on the MCF-7cell cycle with CD44(+)/CD24(-):promoting the G0/G1→G2/S transition.JBreast Cancer.2012,15(4):388–392；Fan L,Xie H,Chen L,et al.AnovelFGF2antagonist peptide P8with potent antiproliferation activity.TumourBiol.2014,35(10):10571–10579；Katoh Y,Katoh M.FGFR2-related pathogenesis andFGFR2-targeted therapeutics.International journal of molecular medicine,2009,23(3):307-311；Matsumoto K,Arao T,Hamaguchi T,et al.FGFR2gene amplificationand clinicopathological features in gastric cancer.British journal of cancer,2012,106(4):727-32；Su X,Zhan P,Gavine PR,et al.FGFR2amplification hasprognostic significance in gastric cancer:results from a large internationalmulticentre study.British journal of cancer,2014,110(4):967-975；L'Hote CG,Knowles MA.Cell responses to FGFR3signalling:growth,differentiation andapoptosis.Experimental cell research.2005,304(2):417-31.)。