CN113198018A - 靶向白三烯受体在胰腺癌治疗组合物中的应用 - Google Patents

靶向白三烯受体在胰腺癌治疗组合物中的应用 Download PDF

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CN113198018A
CN113198018A CN202110488881.6A CN202110488881A CN113198018A CN 113198018 A CN113198018 A CN 113198018A CN 202110488881 A CN202110488881 A CN 202110488881A CN 113198018 A CN113198018 A CN 113198018A
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张志刚
蒋书恒
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Abstract

本发明公开了靶向白三烯受体在胰腺癌治疗组合物中的应用；具体涉及胰腺癌治疗的新靶标以及白三烯受体拮抗剂在胰腺癌治疗中的应用。本发明发现胰腺癌患者使用白三烯受体拮抗剂药物之后，死亡率显著下降。白三烯受体拮抗剂药物具有成为良好靶向药物的潜在应用前景。

Description

靶向白三烯受体在胰腺癌治疗组合物中的应用
技术领域
本发明属于肿瘤治疗技术领域，涉及胰腺癌的治疗领域，具体涉及一种靶向白三烯受体在胰腺癌治疗组合物中的应用。
背景技术
胰腺癌号称“癌中之王”，过去30年针对胰腺癌的治疗都没有显著的进展。患者中位生存期只有半年，5年生存率不足8％[J.D.Mizrahi，R.Surana，J.W.Valle，R.T.Shroff，Pancreatic cancer，Lancet 395(2020)2008-2020.；L.Rahib，B.D.Smith，R.Aizenberg，A.B.Rosenzweig，J.M.Fleshman，L.M.Matrisian，Projecting cancer incidence anddeaths to 2030：the unexpected burden of thyroid，liver，and pancreas cancers inthe United States，Cancer Res 74(2014)2913-2921.]。胰腺癌早期诊断非常困难，早期发现是获得最佳治疗效果的关键，早期胰腺癌手术切除率为90％-100％，5年生存率可达70％-100％，与进展期胰腺癌相比，其治疗效果存在着巨大的反差。但由于胰腺癌早期无明显和特异的症状和体征，以及缺乏简单、可靠的诊断方法，使早期诊断非常困难[S.P.Pereira，L.Oldfield，A.Ney，P.A.Hart，M.G.Keane，S.J.Pandol，D.Li，W.Greenhalf，C.Y.Jeon，E.J.Koay，C.V.Almario，C.Halloran，A.M.Lennon，E.Costello，Earlydetection of pancreatic cancer，Lancet Gastroenterol Hepatol 5(2020)698-710.]；最后，胰腺癌综合治疗效果不理想。由于大部分胰腺癌患者确诊时已属于晚期，失去手术切除机会，辅助性治疗如化疗成为重要的辅助治疗手段，但其疗效及化疗耐药等问题有待进一步研究[A.D.Singhi，E.J.Koay，S.T.Chari，A.Maitra，Early Detection of PancreaticCancer：Opportunities and Challenges，Gastroenterology156(2019)2024-2040.；J.Huang，V.Lok，C.H.Ngai，L.Zhang，J.Yuan，X.Q.Lao，K.Ng，C.Chong，Z.J.Zheng，M.C.S.Wong，Worldwide Burden of，Risk Factors for，and Trends in PancreaticCancer，Gastroenterology 160(2021)744-754.]。
白三烯受体拮抗剂(leukotriene receptor antagonists，LTRAs)，例如孟鲁司特和扎鲁司特，是临床上广泛用于治疗过敏性哮喘的药物[S.E.Dahlen，B.Dahlen，J.M.Drazen，Asthma treatment guidelines meet the real world，N Engl J Med 364(2011)1769-1770.]。除了其在哮喘中的众所周知的作用外，白三烯及其受体介导的信号还参与肿瘤进展以及肿瘤介导的免疫抑制[T.Yokomizo，M.Nakamura，T.Shimizu，Leukotriene receptors as potential therapeutic targets，J Clin Invest 128(2018)2691-2701.]。白三烯受体在多种肿瘤中存在过表达，如结直肠癌、前列腺癌、乳腺癌和胰腺癌等[High Cysteinyl Leukotriene Receptor 1 Expression Correlates withPoor Survival of Uveal Melanoma Patients and Cognate Antagonist DrugsModulate the Growth，Cancer Secretome，and Metabolism of Uveal Melanoma Cells，Cancers(Basel)12(2020).；Cysteinyl leukotriene receptor1facilitatestumorigenesis in a mouse model of colitis-associated colon cancer，Oncotarget8(2017)34773-34786.；A leukotriene B4 receptor-2is associated with paclitaxelresistance in MCF-7/DOX breast cancer cells，Br J Cancer 109(2013)351-359.；Leukotriene B4 receptor antagonist LY293111inhibits proliferation and inducesapoptosis in human pancreatic cancer cells，Clin Cancer Res 8(2002)3232-3242.]。迄今为止，只有很少的体内研究报道了白三烯途径抑制剂的抗肿瘤作用，而在临床层面白三烯受体拮抗剂的作用并不明确。由于一些体外和体内研究提示白三烯受体拮抗剂的潜在抗肿瘤活性，因此发明人利用一项基于瑞典人群的研究，研究了白三烯受体拮抗剂在胰腺癌中的可能作用。
发明内容
本发明的目的在于提供靶向白三烯受体在胰腺癌治疗组合物中的应用。本发明的发明人为了探讨白三烯受体拮抗剂的后续给药与胰腺癌患者死亡率之间的关系，从瑞典国家癌症登记处确定了2006年1月至2015年12月之间诊断为胰腺癌的患者，并将它们与瑞典处方药注册相关联，以确定诊断后的白三烯受体拮抗剂用途。
本发明的目的是通过以下技术方案来实现的：
本发明涉及一种白三烯受体基因或其编码的蛋白的下调剂在制备预防、缓解或治疗胰腺癌的组合物中的用途。
进一步的，所述白三烯受体基因或其编码的蛋白的下调剂选自：核酸抑制物、蛋白抑制剂、蛋白水解酶、蛋白结合分子中的一种或几种.
所述白三烯受体基因或其编码的蛋白的下调剂能够在蛋白或基因水平上下调白三烯受体基因或其编码的蛋白的表达或活性。
本发明还涉及一种用于预防、缓解或治疗胰腺癌的组合物，所述的组合物含有：
(1)白三烯受体基因或其编码的蛋白下调剂；和
(2)药学上可接受的载体/拮抗剂。
本发明还涉及一种筛选预防、缓解或治疗胰腺癌的潜在物质的方法，所述方法包括：
S1、用候选物质处理表达或含有白三烯受体基因或其编码的蛋白的体系；
S2、检测所述体系中白三烯受体基因或其编码的蛋白的表达或活性；
其中，若所述候选物质可降低白三烯受体编码蛋白的表达或活性，则表明该候选物质是预防、缓解或治疗胰腺癌的潜在物质。
进一步的，分别采用测试组和对照组进行步骤S1、S2的操作，所述对照组是不添加所述候选物质的表达或含有白三烯受体基因或其编码的蛋白的体系；比较两组白三烯受体基因或其编码的蛋白的表达或活性，如果测试组中白三烯受体基因或其编码的蛋白的表达或活性在统计学上低于对照组，就表明该候选物是预防、缓解或治疗胰腺癌的潜在物质。
与现有技术相比，本发明不拘泥于任何现有理论的限制。尽管白三烯受体受体的功能研究主要集中于哮喘疾病，但本发明的研究者发现在在胰腺癌患者也发挥了显著地治疗作用。综上所述，抑制白三烯受体的表达或活性，可有效降低胰腺癌死亡的风险，有希望成为胰腺癌治疗的有效靶标。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为抑制或干扰白三烯受体与胰腺癌患者生存/死亡率的作用示意图。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
实施例
使用第十届国际疾病分类(ICD-10)代码(C25)从瑞典国家癌症登记处选择2006年1月至2015年12月之间所有被诊断为胰腺癌的患者。TNM分期系统包括肿瘤大小(T)，淋巴结状态(N)和是否存在转移性疾病(M)，用于将胰腺癌的诊断阶段定义为I期(Tis/T1/T2 N0M0)，阶段II(T1/T2/T3 N1 M0或T3 N0 M0)，阶段III(T1/T2/T3 N2 M0或T4任何N M0)和阶段IV(任何T或N M1)。白三烯受体拮抗剂的处方是通过使用Anatomical TherapeuticChemical(ATC)代码R03DC与瑞典处方药注册簿链接确定的(孟鲁司特是瑞典最常用的药物)。排除癌症诊断前使用孟鲁司特的患者。主要结局是作为主要死亡原因的胰腺癌导致的死亡率，次要结局是总体死亡率。结果数据是从死亡原因登记簿中收集的，其中包括死亡日期和死亡原因。与时间相关的Cox回归用于计算与白三烯受体拮抗剂的诊断后使用相关的死亡率的危险比(HRs)和95％置信区间(CIs)。随访始于诊断为胰腺癌之日，并于结局发生时或随访期结束时(2015年12月)终止，以先到者为准。白三烯受体拮抗剂的使用被建模为时间依赖变量，这意味着在癌症诊断后开具白三烯受体拮抗剂处方的患者已从未暴露的随访期(从诊断胰腺癌到首次分发白三烯受体拮抗剂)至暴露期(从首次分发白三烯受体拮抗剂到随访结束)。
表1显示了LTRA使用者和非LTRA使用者的人口统计学和临床特征。在研究期间，共有25例患者接受了白三烯受体拮抗剂的治疗。与不使用白三烯受体拮抗剂并调整一系列混杂因素的患者相比，接受白三烯受体拮抗剂治疗的患者死于胰腺癌的风险显着降低(HR＝0.56；95％CI，0.32至0.96)，并且总死亡率也降低(HR＝0.66；95％CI，0.41至1.06)(表2，图1)。
Figure BDA0003050366410000041
Figure BDA0003050366410000051
CCl：查尔森合并指数。
Figure BDA0003050366410000052
a校正性别、出生年份、出生国家、诊断时的肿瘤分期、肿瘤诊断时的年龄、阿司匹林和二甲双胍的使用以及查尔森合并指数。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (6)

1.一种白三烯受体基因或其编码的蛋白的下调剂在制备预防、缓解或治疗胰腺癌的组合物中的用途。
2.如权利要求1所述的用途，其特征在于，所述白三烯受体基因或其编码的蛋白的下调剂选自：核酸抑制物、蛋白抑制剂、蛋白水解酶、蛋白结合分子中的一种或几种。
3.如权利要求1所述的用途，其特征在于，所述白三烯受体基因或其编码的蛋白的下调剂能够在蛋白或基因水平上下调白三烯受体基因或其编码的蛋白的表达或活性。
4.一种用于预防、缓解或治疗胰腺癌的组合物，其特征在于，所述的组合物含有：
(1)白三烯受体基因或其编码的蛋白下调剂；和
(2)药学上可接受的载体/拮抗剂。
5.一种筛选预防、缓解或治疗胰腺癌的潜在物质的方法，其特征在于，所述方法包括：
S1、用候选物质处理表达或含有白三烯受体基因或其编码的蛋白的体系；
S2、检测所述体系中白三烯受体基因或其编码的蛋白的表达或活性；
其中，若所述候选物质可降低白三烯受体编码蛋白的表达或活性，则表明该候选物质是预防、缓解或治疗胰腺癌的潜在物质。
6.如权利要求5所述的方法，其特征在于，分别采用测试组和对照组进行步骤S1、S2的操作，所述对照组是不添加所述候选物质的表达或含有白三烯受体基因或其编码的蛋白的体系；比较两组白三烯受体基因或其编码的蛋白的表达或活性，如果测试组中白三烯受体基因或其编码的蛋白的表达或活性在统计学上低于对照组，就表明该候选物是预防、缓解或治疗胰腺癌的潜在物质。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105074469A (zh) * 2013-04-01 2015-11-18 免疫医疗公司 用于胰腺癌早期检测和治疗的抗粘蛋白抗体
CN105408751A (zh) * 2013-10-31 2016-03-16 Sk电信有限公社 用于诊断胰腺癌的组合物以及使用该组合物诊断胰腺癌的方法
WO2020197304A1 (ko) * 2019-03-28 2020-10-01 황정후 테트라스파닌-2 억제제를 유효성분으로 포함하는 췌장암 예방, 개선 또는 치료용 조성물
CN111837197A (zh) * 2018-02-21 2020-10-27 维罗加特斯有限公司 患者评估方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105074469A (zh) * 2013-04-01 2015-11-18 免疫医疗公司 用于胰腺癌早期检测和治疗的抗粘蛋白抗体
CN105408751A (zh) * 2013-10-31 2016-03-16 Sk电信有限公社 用于诊断胰腺癌的组合物以及使用该组合物诊断胰腺癌的方法
CN111837197A (zh) * 2018-02-21 2020-10-27 维罗加特斯有限公司 患者评估方法
WO2020197304A1 (ko) * 2019-03-28 2020-10-01 황정후 테트라스파닌-2 억제제를 유효성분으로 포함하는 췌장암 예방, 개선 또는 치료용 조성물

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