CN115068614A - 用于诊断、治疗和预防癌症的方法和组合物 - Google Patents
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Abstract
本发明涉及通过调节靶基因表达或活性来诊断、治疗或预防癌症的方法,包括上调,沉默和/或下调所述基因。本发明中涉及的靶基因包括FGF;CATSPER4等。本发明还提供了用于诊断、治疗或预防癌症的组合物,包括核酸、抗体,小分子和其他抑制剂等。
Description
技术领域
本发明涉及肿瘤医学和医药领域。具体的,本发明提供了新的肿瘤相关基因及其用于诊断、治疗或预防癌症的方法。本发明还提供了调节相关基因的组合物在治疗癌症或制备治疗癌症的药物中的用途。
背景技术
在过去的几十年中,癌症已成为全球死亡的主要原因。
从化学或放射性治疗等系统性治疗开始,对癌症的治疗领域已发展成针对各种癌症类型的特定细胞生长途径或重新激活免疫系统以对抗癌症的免疫治疗方法的靶向治疗。已经证明,靶向在癌症中具有重要功能作用的特定基因可以导致有效的治疗,例如EGFR抑制剂。
靶向治疗通常集中于停止异常癌细胞生长,例如,CDK4/6抑制剂或重新激活/重新设计肿瘤免疫微环境中的免疫细胞以抑制恶性细胞,例如,PD1/PDL1。尽管在癌症治疗方面取得了快速进展,但大多数这些疗法都是基于对疾病机制/途径的现有理解,包括最初被鉴定为与程序性细胞死亡相关的基因的PD1。在系统和/或细胞水平上的大规模遗传/基因组研究提供了以相对无偏见的方式分析/理解癌症生物学的前所未有的方法和用于理解癌症的新方法。
因此,本领域还需要对癌症的基因影响因素有更多的研究,已获得新的治疗方法或诊断方法。
发明内容
本发明通过新的辨别癌症相关基因的方法鉴别得到新的与癌症相关的基因,并通过实验证明所述基因与癌症相关,由此提供了对新的治疗方法或诊断方法,或是用于判断相关癌症风险的方法。本发明还提供了采用调节所述基因的组合物在治疗和诊断癌症的方法和制备治疗和诊断癌症的药物中的用途。
在本发明的其中一个方面,提供了一种用于治疗或预防哺乳动物的癌症的方法,包括施用能够与基因相互作用的组合物,其中,所述组合物能够调节所述基因的表达或活性,
其中,所述基因为以下基因之一或其任意组合:
FGF;CATSPER4;H2BFWT;KRTAP3-2;或LOC646498。
在本发明中,哺乳动物包括,但不局限于,人,大鼠,小鼠,仓鼠,牛,猪,马,羊,人。
在本发明的其中一个方面,其中所述基因是FGF、CATSPER4(Gene ID号378807)、H2BFWT(Gene ID号158983)、KRTAP3-2(Gene ID号83897)或LOC646498(Gene ID号646498)。
在本发明的其中一个方面,其中所述基因是正离子通道精子相关蛋白4,即CATSPER4(cation channel sperm associated 4),Gene ID号378807。本发明首次发现CATSPER4与癌症相关。本文中CATSPER4包括CATSPER4类似物,是指通过其氨基酸序列的修饰或者可以由天然推导出的或衍生得到的多肽。这样的修饰(modification)、修改(amendment)或变化(change)可包括一个或多个氨基酸的取代、缺失和/或添加。
在本发明的其中一个方面,其中所述基因是FGF。在本发明的其中又一个方面,其中所述基因是FGF19、FGF21或FGF23,优选为FGF21。本发明通过新的辨别癌症相关基因的方法,首次发现FGF与癌症有关。成纤维细胞生长因子(FGF)是在发育中的组织和成体组织中表达的多肽。它们参与一些生理机制,包括例如代谢调节和细胞分化。存在超过20种成纤维细胞生长因子的整个家族(FGF家族)。已知FGF家族的三个成员(包括FGF19、FGF21和FGF23)构成了一个亚家族,起着充当内分泌因子参与代谢调节的作用。
其中,人FGF21基因的Gene ID号是26291。天然人FGF21蛋白的序列可获自UNIPROT数据库,登录号为Q9NSA1。209个氨基酸前体蛋白包括信号肽(氨基酸1-28)和成熟蛋白(氨基酸29-209)。
本发明还首次发现H2BFWT(Gene ID号158983);KRTAP3-2(Gene ID号83897);或LOC646498(Gene ID号646498)与癌症有关。
在本发明的一个方面,所述癌症是血癌。在本发明的另一个方面,所述癌症是实体瘤,例如为尿道、输尿管以及肾盂的尿道上皮细胞癌、多发性骨髓瘤、肾脏癌、乳癌、结肠癌、头颈癌、肺癌、前列腺癌、神经胶母细胞瘤、骨肉瘤、脂肪肉瘤、软组织肉瘤、卵巢癌、黑色素瘤、肝癌、食道癌、胰脏癌或胃癌。
在本发明的其中一个方面,在用于治疗或预防哺乳动物的癌症的方法,采用的与基因相互作用的组合物是核酸。所述核酸是DNA或RNA,能够在哺乳动物体内增强上述基因的数量或表达。
根据本发明的另一方面,将核酸分子导入组织,包括乳腺组织,结肠组织,前列腺组织,皮肤组织,骨组织,腮腺组织,胰腺组织,肾组织,子宫颈组织,肺组织,淋巴结组织,或卵巢组织,其中,所述核酸分子是诱铒分子,诱铒DNA,双链DNA,单链DNA,复合DNA,包囊的DNA,病毒DNA,质粒DNA,裸露的RNA,包囊的RNA,病毒RNA,双链RNA,能够增强目标基因的数量或表达。
所述核酸分子是以裸露的寡核苷酸或载体形式送递。例如,所述核酸是作为载体送递的,其中,所述载体是质粒,粘粒,噬菌体,或病毒,例如,逆转录病毒或基于腺病毒的载体。在本发明的其中一个方面,所述载体包括目标基因的核苷酸序列或是具有与其至少大约90%序列同一性的核苷酸序列,由此增强基因在哺乳动物细胞内,例如人细胞的表达。
在本发明的另一个方面,所述核酸在导入哺乳动物的组织时能够减弱目标基因的表达。例如,所述核酸是干扰RNA,例如为siRNA,RNAi或shRNA或能够编码siRNA,RNAi或shRNA的分子,其能够在哺乳动物体内导致例如CATSPER4的转录后沉默。
在本发明中,可导致CATSPER4的转录后沉默的干扰RNA的靶序列(即所述干扰RNA识别的目标基因的mRNA序列)以及用于构建siRNA或shRNA的正义链序列和反义链序列对如下表3所示。其中每一列显示一个siRNA的正义链序列和反义链序列对,以及该siRNA对应的CATSPER4的mRNA序列。
表3用于CATSPER4的siRNA的正义链序列和反义链序列对,以及其识别的CATSPER4基因上的靶序列。
在本发明的其中一个方面,本发明提供的用于治疗或预防哺乳动物的癌症的方法中,所述核酸是干扰RNA,其针对CATSPER4的靶序列为如表3记载的靶序列中的任何一个。在本发明的其中又一个方面,所述干扰RNA为siRNA或shRNA,每个所述siRNA或shRNA具有如表3记载的正义链序列和反义链序列对中的任何一个。
在本发明的其中又一个方面,所述干扰RNA为siRNA,其具有以下正义链序列和反义链序列对:
正义链序列和反义链序列对a.正义链(5'-3'):CUCUUGCGGUUCUUCAUUAAU(SEQ IDNO:1);和反义链(5'-3'):UAAUGAAGAACCGCAAGAGCA(SEQ ID NO:2);
正义链序列和反义链序列对b.正义链(5'-3'):GGUGCCUGACAUGGCCAAUAU(SEQ IDNO:3);和反义链(5'-3'):AUUGGCCAUGUCAGGCACCGA(SEQ ID NO:4);
或
正义链序列和反义链序列对c.正义链(5'-3'):UCAUGACUCUAGCUCACAAAU(SEQ IDNO:5);和反义链(5'-3'):UUGUGAGCUAGAGUCAUGAAC(SEQ ID NO:6)。
在本发明中,所述组合物包括核酸的递送系统,例如为外泌体(天然或人工制备得到的外泌体)、脂质体或带细胞穿透肽(cell penetration peptide,CPP)的脂质体、病毒载体。
在本发明的其中一个方面,在用于治疗或预防哺乳动物的癌症的方法,采用的与基因相互作用的组合物是多肽,其具有所述基因在哺乳动物体内表达产物的活性或能够增强所述基因在哺乳动物体内表达产物的活性。
本发明的其中另一个方面,在用于治疗或预防哺乳动物的癌症的方法,采用的与基因相互作用的组合物是多肽,其具有所述基因在哺乳动物体内表达产物的活性或能够降低所述基因在哺乳动物体内表达产物的活性。例如,所述多肽是抗体,其特异性识别所述基因在哺乳动物体内表达产物。
在本发明的其中一个方面,在用于治疗或预防哺乳动物的癌症的方法,采用的与基因相互作用的组合物是小分子,所述小分子能与目标基因,相互作用,并因此增强其表达或活性。
在本发明的其中一个方面,在用于治疗或预防哺乳动物的癌症的方法,采用的与基因相互作用的组合物是小分子,所述小分子能与目标基因例如CATSPER4,相互作用,并因此减弱其表达或活性。
可以通过筛选方法得到上述用于治疗或预防哺乳动物的癌症的组合物,包括所述核酸,多肽后小分子。
在本发明的另一个方面,提供的所述筛选方法可包括以下步骤:
(a)使待测组合物与目标基因表达的多肽接触;
(b)检测待测组合物与所述多肽的结合活性。
所述筛选方法还可包括以下步骤:
(c)检测步骤(a)的多肽的活性,与步骤(b)的结合多肽的活性进行比较。
在本发明的另一个方面,提供了筛选用于治疗或预防哺乳动物的癌症的组合物的方法,包括以下步骤:
(a)使待测组合物与表达以下基因的细胞或动物接触;
(b)检测所述基因表达所述多肽的数量或活性。
本发明还提供了用于治疗或预防癌症的药物组合物。本发明的药物组合物中含有前述与基因相互作用的组合物作为活性成份,其中,所述组合物能够调节所述基因的表达或活性,其中,所述基因为:
FGF;CATSPER4;H2BFWT;KRTAP3-2;或LOC646498。
在本发明的其中一个方面,其中所述基因是CATSPER4。
所述组合物为前面描述的核酸、多肽和小分子等。
本发明的药物组合物中的活性成分可以以原料化合物的形式给药,另外也可将活性成分,任选地以生理上可接受的盐的形式,与一种或多种佐剂、赋形剂、载体、缓冲剂、稀释剂和/或其他常规的药物辅料一起引入药物组合物。
可以通过任意便利的适合于期望疗法的途径给予本发明的药物组合物。优选的给药途径包括口服给药,特别是以片剂、胶囊、锭剂、散剂和液体形式;和胃肠外给药,特别是皮肤、皮下、肌内和静脉内注射。本发明的药物组合物可以由本领域技术人员通过使用适合于期望制剂的标准方法和常规技术制备。如果需要,则可以使用适合于使活性成分缓释的组合物。
在本发明中,核酸的递送系统可为外泌体(天然或人工制备得到的外泌体)、脂质体(例如带CPP的脂质体)或病毒载体。
本发明还提供了前述与所述基因相互作用的组合物在制备用于治疗或预防癌症的药物组合物中的用途。
本发明还提供了一种用于诊断哺乳动物的癌症的方法,包括检测所述基因的表达或活性的变化。
本发明还提供了一种用于判断哺乳动物患癌症的风险方法,包括检测所述基因的表达或活性的变化。在本发明的其中一个方面,判断哺乳动物患癌症的风险包括其获得所述癌症的风险,以及患有所述癌症的风险等。
上述本发明的诊断哺乳动物的癌症的方法或判断哺乳动物患癌症的风险的方法中,所述基因为以下基因之一或其任意组合:
FGF;CATSPER4;H2BFWT;KRTAP3-2;或LOC646498。
在本发明的其中一个方面,上述方法中所述基因是CATSPER4。
在本发明的其中一个方面,所述基因,例如CATSPER4的表达可以通过本领域已知的任何检测样品中蛋白质(表达)的方法进行检测。所述方法可以检查CATSPER4的存在或不存在。所述方法也可以定量检测CATSPER4的表达的量。
在本发明中,可以通过采用抗体的方法进行检测,其特异性识别所述基因表达的多肽。
在本发明中可用的检测样品中蛋白质(表达)的方法包括免疫测定(immunoassay)。例如通过特异性识别CATSPER4的抗体进行ELISA或蛋白质印迹。抗体可以是单克隆或多克隆的。抗体可以是人源化或嵌合的。
在本发明中可用的诊断方法还包括检测所述基因,例如CATSPER4,的mRNA的存在或其数量,例如通过RT-PCR检测样品中CATSPER4的mRNA或其片段的量。检测CATSPER4的mRNA的RT-PCR方法和条件是本领域技术人员已知或容易获得的。
本发明还提供了通过上述本发明的方法来诊断哺乳动物的癌症或判断哺乳动物患癌症的风险的试剂盒。所述试剂盒,包括用于检测所述基因的表达或活性的变化的制剂。
在本发明的其中一个方面,其中所述基因是CATSPER4。
在本发明的其中又一个方面,所述试剂盒中包括在样品中检测所述基因,例如CATSPER4,的试剂。所述试剂例如为免疫测定所述基因的蛋白产物的量的试剂,如特异性识别的抗体。或所述试剂例如为检测所述基因的mRNA的存在或其数量的试剂,如用于RT-PCR检测mRNA的量的试剂(例如序列特异性引物)。
在本文中,蛋白符号不用斜体,并全部大写;基因符号使用斜体。但有时在本文中基因符号也不使用斜体。例如有时本文中的“CATSPER4”,既代表基因,也代表该基因的表达产物。
具体实施方式
实施例1通过临床样品大数据分析和筛选潜在的癌症相关基因
通过对临床样品进行大数据分析,筛选潜在的癌症相关基因。在本发明中进一步研究的潜在的癌症相关基因包括:FGF;CATSPER4;H2BFWT;KRTAP3-2;LOC646498。
实施例2定量RT-PCR检测CATSPER4在癌细胞中的表达
对潜在的癌症相关基因进行蛋白表达检测,观察其在正常细胞和癌细胞中的表达。
根据已公开的数据,CATSPER4在正常人的组织样品中,只在睾丸组织中有表达,而在除睾丸以外的组织(小肠、十二指肠、骨髓、子宫内膜、食道、脂肪组织、膀胱、心脏、肾脏、淋巴、卵巢、胰脏、前列腺等)都检测不到其表达。
发明人在癌细胞中验证CATSPER4在癌组织或癌细胞中的表达。
将人肾上皮细胞系H293T细胞培养24到48小时,从收集的细胞中提取总RNA并纯化。采用LightCycler 480InstrumentII进行定量RT-PCR。
使用的引物信息如下:
CATSPER4引物对:正向引物5′-GGTGCCATCTACTTTACCATCT-3′和反向引物5′-GCTCTCCTGCCTTCATCATT-3’。
GAPDH对照:引物对:正向引物5′-GTCTCCTCTGACTTCAA-3′和反向引物5′-ACCACCCTGTTGCTG-3’。
所有RT-PCR反应均在94℃下初始变性2分钟,然后进行40个循环:在94℃下变性15秒,在60℃下退火、延伸和荧光读数,1分钟。
结果如下表1:
表1:qPCR验证基因在H293T细胞中的表达
结果显示,CATSPER4在H293T中有高的表达。
发明人在其它癌细胞系中对CATSPER4的表达进行了检测。结果如下表4所示。
表4不同组织中CATSPER4的相对表达
组织 | 细胞株 | 相对表达倍数 |
胰腺 | PK59 | 3.1 |
肺 | SALE | 3.0 |
造血和淋巴组织 | A3KAW | 2.8 |
卵巢 | OVISE | 2.7 |
皮肤 | IGR1 | 2.6 |
子宫内膜 | HEC6 | 2.5 |
乳腺 | MDAMB415 | 2.4 |
上消化道 | SNU1066 | 2.3 |
胃 | MKN74 | 2.3 |
中枢神经系统 | F5 | 2.2 |
大肠 | SNUC2A | 2.2 |
胆 | SNU869 | 2.2 |
食管 | KYSE30 | 2.1 |
前列腺 | VCAP | 1.8 |
泌尿系统 | RT112 | 1.6 |
骨 | U2OS | 1.5 |
肝 | HUH6 | 1.4 |
自主神经结 | SKNDZ | 1.3 |
软组织 | CME1 | 1.2 |
唾液腺 | A253 | 1.2 |
甲状腺 | BHT101 | 1.0 |
结果显示,CATSPER4在其它癌细胞系中都检测到明显表达。CATSPER4在癌症细胞的高表达与其在正常细胞的不表达(或检测不到其表达)形成了鲜明比较。其中,在肾癌、胰腺癌,肺癌的细胞中表达较高。
可见,CATSPER4可以作为判断癌症,例如肾癌、胰腺癌,肺癌等的风险的标志物。
另外,CATSPER4可以作为癌症,例如肾癌、胰腺癌,肺癌等的标志物。进而可以作为癌症治疗的靶点,例如用于ADC技术,或者定向的药物输送、以及核酸治疗。
实施例3CATSPER4表达水平的下调
采用siRNA在H293T中下调CATSPER4的表达水平。
构建3个CATSPER4的siRNA(购自于北京擎科新业生物技术有限公司)。采用脂质体法转染H293T 48小时,观察其对CATSPER4的表达的影响。
三个siRNA序列如下:
siRNA1:正义链(5′-3′):CUCUUGCGGUUCUUCAUUAAU;和反义链(5′-3′):UAAUGAAGAACCGCAAGAGCA;
siRNA2:正义链(5′-3′):GGUGCCUGACAUGGCCAAUAU;和反义链(5′-3′):AUUGGCCAUGUCAGGCACCGA
siRNA3:正义链(5′-3′):UCAUGACUCUAGCUCACAAAU;和反义链(5′-3′):UUGUGAGCUAGAGUCAUGAAC。
结果如下表2:
表2:qPCR检测基因在H293T细胞中siRNA转染后的表达
结果表明,siRNA用于H293T的转染,使H293T中CATSPER4的表达降低。其中,siRNA3转染H293T细胞后,与GAPDH的Ct值相差2.55,同样细胞的对照实验中(无siRNA转染),CATSPER4与GAPDH的平均Ct值相差1.55,提示siRNA使该基因表达降低大概2倍左右。
实施例4在动物模型中减弱CATSPER4的表达
将实施例3中制备的shRNA导入癌症动物模型,观察对癌症组织细胞中的CATSPER4的表达以及对癌症组织的抑制情况。
实施例5在动物模型中敲除CATSPER4基因
制备敲除CATSPER4基因的哺乳动物模型,然后用癌症细胞株进行接种,观察肿瘤生成情况。
实施例6影响CATSPER4表达的小分子筛选实验
培养细胞株,在培养液中加入候选小分子,经过指定时间后,测定培养的细胞中CATSPER4的表达,选择对CATSPER4有调节作用的小分子做下一步分析。
如无特别表示,本文中出现的温度的单位“度”是指摄氏度,即℃。
序列表
<110> 胡晓兰
<120> 用于诊断、治疗和预防癌症的方法和组合物
<160> 6
<170> PatentIn version 3.5
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<212> RNA
<213> 人工序列
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uaaugaagaa ccgcaagagc a 21
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<213> 人工序列
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ggugccugac auggccaaua u 21
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<213> 人工序列
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auuggccaug ucaggcaccg a 21
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ucaugacucu agcucacaaa u 21
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uugugagcua gagucaugaa c 21
Claims (10)
1.一种用于治疗或预防哺乳动物的癌症的方法,包括施用能够与基因相互作用的组合物,其中,所述组合物能够调节所述基因的表达或活性,
其中,所述基因为以下基因之一或其任意组合:
FGF;
CATSPER4;
H2BFWT;
KRTAP3-2;或
LOC646498,
优选的,所述基因为CATSPER4。
2.如权利要求1的方法,其中,所述癌症是血癌或实体瘤,例如为尿道、输尿管以及肾盂的尿道上皮细胞癌、多发性骨髓瘤、肾脏癌、乳癌、结肠癌、头颈癌、肺癌、前列腺癌、神经胶母细胞瘤、骨肉瘤、脂肪肉瘤、软组织肉瘤、卵巢癌、黑色素瘤、肝癌、食道癌、胰脏癌或胃癌。
3.如权利要求1的方法,其中,所述组合物是核酸,例如为DNA或RNA。
4.如权利要求3的方法,其中,所述核酸是干扰RNA,例如所述干扰RNA为siRNA或shRNA,更优选的,其具有以下正义链序列和反义链序列对:
a.正义链(5'-3'):CUCUUGCGGUUCUUCAUUAAU;和反义链(5'-3'):UAAUGAAGAACCGCAAGAGCA;
b.正义链(5'-3'):GGUGCCUGACAUGGCCAAUAU;和反义链(5'-3'):AUUGGCCAUGUCAGGCACCGA;
或
c.正义链(5'-3'):UCAUGACUCUAGCUCACAAAU;和反义链(5'-3'):UUGUGAGCUAGAGUCAUGAAC。
5.如权利要求3的方法,其中,所述组合物包括核酸的递送系统,例如为外泌体(天然或人工制备得到的外泌体)、脂质体或带细胞穿透肽(cell penetration peptide,CPP)的脂质体、病毒载体。
6.一种用于判断哺乳动物的癌症风险的方法,包括检测所述基因的表达或活性的变化,
其中,所述基因为以下基因之一或其任意组合:
FGF;
CATSPER4;
H2BFWT;
KRTAP3-2;或
LOC646498,
优选的,其中所述基因是CATSPER4。
7.如权利要求6的方法,其中,包括检测所述基因的mRNA。
8.一种用于判断哺乳动物癌症风险的试剂盒,包括用于检测所述基因的表达或活性的变化的制剂,
其中,所述基因为以下基因之一或其任意组合:
FGF;
CATSPER4;
H2BFWT;
KRTAP3-2;或
LOC646498,
优选的,其中含有可检测所述基因的mRNA的制剂,例如序列特异性引物;
或者,其中含有可检测所述基因表达的多肽的制剂,例如特异性抗体。
9.一种用于治疗或预防哺乳动物的癌症的药物组合物,其含有能够与基因相互作用的组合物,其中,所述组合物能够调节所述基因的表达或活性,
其中,所述基因为以下基因之一或其任意组合:
FGF;
CATSPER4;
H2BFWT;
KRTAP3-2;或
LOC646498,
优选的,其中所述基因是CATSPER4。
10.如权利要求9的药物组合物,其中,所述组合物是核酸,(例如为DNA或RNA),例如所述核酸为干扰RNA,优选的,所述干扰RNA为siRNA或shRNA,更优选的,其具有以下正义链序列和反义链序列对:
a.正义链(5'-3'):CUCUUGCGGUUCUUCAUUAAU;和反义链(5'-3'):UAAUGAAGAACCGCAAGAGCA;
b.正义链(5'-3'):GGUGCCUGACAUGGCCAAUAU;和反义链(5'-3'):AUUGGCCAUGUCAGGCACCGA;
或
c.正义链(5'-3'):UCAUGACUCUAGCUCACAAAU;和反义链(5'-3'):
UUGUGAGCUAGAGUCAUGAAC。
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