CN111417730A - 诊断方法 - Google Patents
诊断方法 Download PDFInfo
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- CN111417730A CN111417730A CN201880074841.3A CN201880074841A CN111417730A CN 111417730 A CN111417730 A CN 111417730A CN 201880074841 A CN201880074841 A CN 201880074841A CN 111417730 A CN111417730 A CN 111417730A
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- Prior art keywords
- hydrochloride
- cancer
- inhibitor
- acetate
- chemical
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Abstract
本发明属于癌症诊断领域。确切地说,本发明涉及一种用于在癌症患者中测定产生对癌症疗法中使用的化学物质的抗性的风险的方法。此外,本发明提供一种用于已经诊断为产生针对用于治疗癌症的化学物质的抗药性的患者的新颖组合疗法。
Description
技术领域
本发明属于癌症诊断领域。确切地说,本发明涉及一种用于在癌症患者中测定产生对癌症疗法中使用的化学物质的抗性的风险的方法。此外,本发明提供一种用于已经诊断为产生针对用于治疗癌症的化学物质的抗药性的患者的新颖组合疗法。
背景技术
癌细胞的基因改变通常影响对细胞周期控制、增殖、分化和/或信号转导重要的基因。(Hanahan,D.,Weinberg,R.A.《细胞(Cell)》100,57-70(2000);Hanahan,D.,Weinberg,R.A.《细胞》144,646-674(2011))。MAPK路径的肿瘤原性活化是许多人类癌症的标志特征,所述人类癌症包含黑素瘤、非小细胞肺癌(NSCLC)和胰腺癌。(Dhillon,A.S.等人,《癌基因(Oncogene)》26,3279-3290(2007))。举例来说,50-70%的黑素瘤由活化组成性MAPK信号传导的BRAF-V600E癌蛋白引起。(Davies,H.等人,《自然(Nature)》417,949-954(2002))。单独或与MEK抑制剂组合的BRAF抑制剂显著增加患者存活率,但临床反应通常持续时间有限。(Flaherty,K.T.等人,《新英格兰医学杂志(N.Engl.J.Med.)》363,809-819(2010);Chapman,P.B.等人,《新英格兰医学杂志》364,2507-2516(2011);Hauschild,A.等人,《柳叶刀(Lancet)》380,358-65(2012);Flaherty,K.T.等人,《新英格兰医学杂志》367,1694-1703(2012);Larkin,J.等人,《新英格兰医学杂志》371,1867-1876(2014);Long,G.V.等人,《新英格兰医学杂志》371,1877-1888(2014);Robert,C.等人,《新英格兰医学杂志》372,30-39(2015);Long,G.V.等人,《柳叶刀》386,444-451(2015))。
已发现表型和信号传导可塑性以及新颖基因改变的获取是对癌症治疗中的产生对靶向抑制剂的抗性中的驱动因素。(Engelman,J.A.等人,《科学(Science)》316,1039-1043(2007);Kugel,C.H.等人,《癌症研究(Cancer Res.)》74,4122-4132(2014);Goetz,E.M.等人,《癌症研究》74,7079-7089(2014);Hartsough,E.、Shao,Y.、Aplin,A.E.,《研究性皮肤病学杂志(J.Invest.Dermatol.)》134,319-325(2014);Roesch,A.等人,《欧洲癌症杂志(Eur.J.Cancer)》59,109-112(2016))。抗药性肿瘤的基因全景的不可预测的肿瘤间和肿瘤内不均匀性使预防对于靶向疗法的抗性的临床试验的设计复杂化。(Romano,E.,《临床癌症研究(Clin.Cancer Res.)》19,5749-5757(2013);Shi,H.等人,《癌症发现(CancerDiscov.)》4,80-93(2014);Van Allen,E.M等人,《癌症发现》4,94-109(2014);Roesch,A.,《癌基因》34,2951-2957(2015);Shaffer S.M.等人,《自然》564,431-435(2017))。
用使用靶向抑制剂与额外药物的组合的新颖疗法增加患者存活率的当前方法时常在未经选择的患者群体上使用,或由癌细胞相较于正常细胞,或对药物敏感的癌细胞到抗药性癌细胞的基础基因表达模式引导。(Evans,W.E.,Relling,M.V.,《自然》429,464-468(2014);Glinsky,G.V.,《干细胞评论(Stem Cell Rev.)》3,79-93(2007);Johannessen,C.M.等人,《自然》504,38-42(2013))。癌细胞响应于药物治疗的适应性转录变化和肿瘤内和肿瘤间不均匀性限制了这些方法的临床功效。在WO 2009/151503中描述了克服先前所观测到的缺点的一种方法。其中提供一种鉴别如对用常规疗法进行的治疗具有抗性的瘤形成的方法。所述方法涉及鉴别来源于目前进行瘤形成的医药治疗的患者的样品中的各种标记物的含量增加。因此,患者已经接受常规治疗。然而,癌症治疗可以诱发癌细胞变化并且由此引起抗药性。(Smith,M.P.,《癌细胞(Cancer Cell)》29,270-284(2016))。这意味着所描述的方法不能够在患者暴露于常规疗法之前鉴别潜在地处于产生抗性的风险下的患者。
因此,需要提供在癌症患者中可靠地测定产生对给定化学物质的抗性的风险的手段和方法,所述方法可以用于个性化癌症疗法以鉴别适合于长期治疗策略的患者。
本发明现在满足此需求,因为其提供此类手段和方法,其在本发明的权利要求书和以下实施例中进行更特定地定义。
发明内容
在一个实施例中,本发明提供一种用于测定细胞(确切地说,癌细胞或肿瘤细胞)是否将对化学物质产生抗性的方法,其中所述方法包括以下步骤:
a)将包括或由从诊断患有癌症的个体获得的癌细胞或肿瘤细胞组成的一个或多个样品暴露于化学物质,其中所述诊断患有癌症的个体先前未给予过所述化学物质;
b)测定a)中所使用的一个或多个样品中与产生癌症药物抗性相关的基因的表达量;
c)测定来自诊断患有癌症的个体的一个或多个样品中与b)中相同的基因的表达量,所述样品未暴露于a)中所用的化学物质;
其中b)中测定的表达量与c)中测定的表达量相比升高指示所述样品中所包括的癌细胞或肿瘤细胞对化学物质产生抗性。
因此,本发明人出乎意料地并且意外地发现可在活体外分析从诊断患有癌症的个体获得的样品中所包括的细胞,确切地说,癌细胞或肿瘤细胞,以测定样品中所包括的细胞,确切地说,癌细胞或肿瘤细胞是否将对化学物质(确切地说,用于治疗癌症的物质)产生抗性。特定来说,尚未知晓或有迹象表明与产生癌症相关的基因的表达可以通过活体外方法中的化学物质诱导。所属领域中已知的先前方法利用在患者已经对化学物质产生抗性之后取自患者的样品中,与在患者对化学物质产生抗性之前,或在患者仍在临床上对所述物质敏感时取自患者的样品中的基因标签相比发生改变的基因标签。如发明人已发现,药物暴露可剧烈影响针对治疗中所使用的化学物质的抗性的潜在产生的任何后续分析。本发明的方法通过使用来源于在获得一个或多个样品之前不接受治疗的个体的样品克服了此缺点。
根据上文,本发明另外提供一种用于测定先前诊断患有癌症的个体是否将对用于治疗所述癌症的化学物质产生抗性的方法,其中所述方法包括以下步骤:
a)将包括或由从诊断患有癌症的个体获得的癌细胞或肿瘤细胞组成的一个或多个样品暴露于化学物质,其中所述诊断患有癌症的个体先前未给予过所述化学物质;
b)测定a)中所使用的一个或多个样品中与产生癌症药物抗性相关的基因的表达量;
c)测定来自诊断患有癌症的个体的一个或多个样品中与b)中相同的基因的表达量,所述样品未暴露于a)中所用的化学物质;
其中b)中测定的表达量与c)中测定的表达量相比升高指示患者对化学物质产生抗性。
类似于用于测定细胞(确切地说,癌细胞或肿瘤细胞)是否将对化学物质产生抗性的以上方法,所述方法可以用于测定已经诊断患有癌症的个体是否将对用于治疗所述癌症的化学物质产生抗药性。本发明的方法具有意外且出人意料的可在给予化学物质之前采用,且由此避免诱发抗药性的优点。为了避免此类诱发,可以在活体外分析样品,其中在暴露于化学物质之前获得一个或多个样品。因此,如果活体外分析引起产生抗药性的风险升高,那么可以通过应用使用在根据本发明的活体外分析中未展示产生抗药性的风险增加的化学物质的替代性治疗,或通过实行根据本发明的组合治疗或疗法,来预防使用此类化学物质的治疗诱发抗性。
在各种实施例中,本发明涉及根据如本文所述的前述实施例中的任一个的方法,其中样品选自由从肿瘤活检获得和从血液中的循环肿瘤细胞获得的样品组成的群组。
在各种其它实施例中,本发明涉及根据如本文所述的前述实施例中的任一个的方法,其中与产生抗性相关的基因是选自由以下组成的群组的基因:SOX2、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
在本发明的一个特定实施例中,与产生抗性相关的基因为SOX2。
也称为SOX2的性别决定区Y(SRY)-盒2为维持未分化胚胎干细胞的自我更新或多能性所必需的转录因子。蛋白质为转录因子的Sox家族的成员,所述转录因子已展示在哺乳动物发育的许多阶段中起关键作用。举例来说,Sox2控制支气管树的分支形态发生和肺发育中气道上皮的分化。在正常条件下,Sox2对于维持成年气管上皮中的基底细胞的自我更新和适当比例是至关重要的。然而,其过度表达引起大规模上皮增生并且最终在发育中和成年小鼠肺中产生癌瘤。此外,在鳞状细胞癌中,基因扩增经常靶向3q26.3区域。Sox2的基因位于此区域内,这有效地将Sox2表征为癌基因。Sox2为肺鳞状细胞癌中的关键上调因子,其引导肿瘤进展中所涉及的许多基因。Sox2过度表达与Lkb1表达的损失协作以促进小鼠中的鳞状细胞肺癌。其过度表达还活化细胞迁移和非锚定依赖性生长。还在高格里森级(highgleason grade)前列腺癌中发现Sox2表达,并且其促进去势抗药性前列腺癌生长。Sox2还已经展示与乳癌中产生他莫昔芬(Tamoxifen)抗性有关。尽管存在关于与产生癌症相关的基因(如SOX2)的知识,但先前尚未知晓,可以通过添加化学物质在活体外诱导高于天然表达量的此类基因的表达,并且所诱导的过度表达指示针对所应用化学物质产生抗性。
在各种其它实施例中,本发明涉及根据如本文所述的前述实施例中的任一个的方法,其中癌症为黑素瘤、非小细胞肺癌、前列腺癌、胆管癌、膀胱癌、胰腺癌、甲状腺癌、卵巢癌、结肠直肠肿瘤、毛状细胞白血病、急性骨髓白血病、多发性骨髓瘤、肝癌、乳癌、食道癌、头颈癌和神经胶质瘤,并且其中由罹患以上癌症中的任一个的患者获得的样品包括或由相应癌症或肿瘤的细胞组成。
在一个特定实施例中,癌症为黑素瘤和/或非小细胞肺癌。
如本文所用,术语“黑素瘤”是指从黑素细胞发展的癌症类型。黑素瘤通常在皮肤中出现,但可能罕见地在口、肠或眼中出现,所有这些都由本发明涵盖。黑素瘤的主要起因为具有低含量皮肤色素的人群受到的紫外光(UV)暴露。UV光可以来自太阳或来自其它来源,例如晒黑装置。其也可能从痣发展而来。具有许多痣、有家庭成员受黑素瘤影响史和免疫功能较差的人群的风险较大。多种基因缺陷,如引起着色性干皮病(xerodermapigmentosum)的那些基因缺陷也增加产生黑素瘤的风险。诊断可以通过活检任何有关皮肤病变来进行。黑素瘤的预防一般涉及使用防晒剂和避开UV光。最常见的治疗为通过手术去除。然而,可以测试个体(确切地说,患有稍大型癌症的个体)的扩散。个体,确切地说,黑素瘤扩散的个体可能需要免疫疗法、生物疗法、放射疗法和/或化学疗法。尽管所属领域中可用各种治疗选项,但黑素瘤仍是最危险的皮肤癌类型。在2012年,全球的黑素瘤新病例为232,000人。2015年,有310万人患有活动性疾病,其中引起59,800人死亡。可使用各种化疗剂(包含替莫唑胺(temozolomide)、达卡巴嗪(dacarbazine)(也称为DTIC))、免疫疗法(使用白介素-2(IL-2)或干扰素(IFN))以及局部灌注。然而,转移性黑素瘤的总体成功率非常有限。IL-2(普罗金(Proleukin))也已经展示为用于黑素瘤疗法的有价值目标。研究已证实,IL-2提供完全和长效缓解这种疾病的可能性。包含生物免疫疗法试剂,其包含例如伊匹单抗(ipilimumab)、派立珠单抗(pembrolizumab)和/或纳武单抗(nivolumab);BRAF抑制剂,如维罗非尼(vemurafenib)和达拉非尼(dabrafenib);以及MEK抑制剂,如曲美替尼(trametinib)和/或考比替尼(cobimetinib)的转移性黑素瘤的疗法也可用于治疗黑素瘤。然而,癌细胞(尤其黑素瘤细胞)可对治疗中所使用的可用化学物质产生抗性。因此,需要提供不会引起产生抗性的疗法选项或提供可靠地预测个体是否将对用于治疗黑素瘤的化学物质产生抗性的方法。如上文所详述,本发明提供一种可靠的方法,其用于测定诊断患有癌症(尤其黑素瘤)的个体是否将对用于治疗癌症(尤其黑素瘤)的化学物质产生抗性,所述化学物质如上文所述的化学物质。因此,在一些实施例中,本发明涉及通过使用先前未展示引起所述个体产生抗性的化学物质来治疗个体的黑素瘤的方法。本发明的方法是有利的,因为个体先前未接受此类治疗并且因此先前未产生抗性。
在本发明的其它实施例中,个体已经诊断患有非小细胞肺癌(NSCLC)。NSCLC占所有肺癌的约85%并且因此是一项主要威胁。目前,与小细胞癌和其它类型的癌症相比,NSCLC对化学疗法相对较不敏感。尽管化学疗法越来越多地在术前(新辅助化学疗法)和术后(辅助化学疗法)使用,但在可能的情况下,它们主要通过以治愈为目的的手术切除术来治疗。最常见类型的NSCLC是鳞状细胞癌、大细胞癌和腺癌,但存在发病频率较低的若干其它类型,并且所有类型可以不寻常的组织学变体和混合细胞类型组合形式出现。
取决于癌症的阶段、个体的总体健康状况、年龄、对化学疗法的反应以及如治疗的可能副作用的其它因素,一般使用多于一种治疗。技术人员熟知可用的治疗。然而,在完全分期后,NSCLC患者通常可以分类为三种不同类别中的一种:患有早期非转移性疾病(I期、II期和选择III期肿瘤)的患者、患有限于胸腔的局部晚期疾病的患者(例如大型肿瘤、涉及关键胸部结构的肿瘤或患有阳性纵隔淋巴结的患者)或具有超出胸腔范围的远端癌转移的患者。NSCLC通常对化学疗法和/或放射不是很敏感。然而,存在可由所属领域的技术人员选择的多种可能的化疗剂。大多数将涉及基于铂的化学疗法药物顺铂。然而,存在广泛多种化学疗法选项以用于晚期(转移性)NSCLC。这些试剂包含两种传统化学疗法,如顺铂,其无差别地靶向所有快速分裂细胞;以及较新的靶向试剂,其更针对于患者肿瘤内出现的特定基因畸变。目前,存在在NSCLC肿瘤中常规地分析概况以指导进一步治疗决策的两种基因标记物:EGFR和间变性淋巴瘤激酶内的突变。还存在多种已知在NSCLC内突变并且可影响将来的治疗的额外基因标记物,包含BRAF(基因)、HER2/neu和KRAS。
重要地,大约10-35%的NSCLC患者将具有EGFR的药物敏化突变。已发现多种不同EGFR突变,然而,某些畸变将产生蛋白质的活性过高形式。具有这些突变的患者更有可能具有腺癌组织结构并且不吸烟或吸烟较少。这些患者已经展示对称为酪氨酸激酶抑制剂的阻断EGFR蛋白质的某些药品(确切地说,埃罗替尼(erlotinib)、吉非替尼(gefitinib)或阿法替尼(afatinib))敏感。当暴露于EGFR抑制剂时,SOX2已展示在经培养的NSCLC细胞系中转录诱导。由于诊断技术的可变灵敏度,肺癌中突变的可靠鉴别需要谨慎考虑。在替代方案中,至多7%的NSCLC患者的ROS1基因中的EML4-ALK易位或突变;这些患者可受益于所属领域的技术人员已知的ALK抑制剂。克卓替尼(crizotinib)是若干激酶,确切地说,ALK、ROS1和MET的已知抑制剂。
未发现具有EGFR或ALK突变的患有晚期疾病的NSCLC患者可以接受贝伐单抗(bevacizumab),其为靶向针对血管内皮生长因子(VEGF)的单克隆抗体药品。这是基于一项美国东部肿瘤协作组(Eastern Cooperative Oncology Group)研究,其发现向患有复发性或晚期非小细胞肺癌(IIIB期或IV期)的某些患者的卡铂和太平洋紫杉醇(paclitaxel)化学疗法中添加贝伐单抗可以增加整体存活期和无进展存活期。另一治疗选项为在肿瘤表达PD-L1和用其它化学治疗剂治疗失败的患者中,用于晚期或转移性鳞状细胞癌的抗PD-1剂纳武单抗,或用于治疗转移性非小细胞肺癌(NSCLC)的派立珠单抗。
如果癌症过度表达PDL1并且癌症不具有EGFR或ALK的突变,那么派立珠单抗变成待用于NSCLC一线治疗的第一免疫疗法;如果已经给予化学疗法,那么派立珠单抗可以用作二线治疗,但如果癌症具有EGFR或ALK突变,那么应该首先使用靶向那些突变的试剂。必须与经过验证和批准的伴随诊断一起进行PDL1的评估。然而,在所有这些治疗选项中,需要测定在治疗之前产生抗性的可能性。在黑素瘤中,MAPK靶向疗法诱导与在对于抗PD-1疗法具有固有抗性的肿瘤中检测到的基因表达变化类似的基因表达变化。(Hugo,W.,《细胞》165,35-44(2016))。本发明方法通过使用在治疗之前来源于患者的一个或多个样品提供此类有利的测定。
根据上文,在各种其它实施例中,本发明涉及根据如本文所述的前述实施例中的任一个的方法,其中所述化学物质为受体酪氨酸激酶(RTK)的抑制剂、EGFR路径的抑制剂(EGFRi)、检查点激酶的抑制剂、MAPK路径的抑制剂(MAPKi)或免疫疗法中使用的试剂,其中优选地,所述MAPKi为B-Raf的抑制剂(BRAFi)、MEK的抑制剂(MEKi)或ERK的抑制剂(ERKi)。化学物质还可以是用于癌症的免疫疗法中的试剂,确切地说,免疫肿瘤学试剂。
在各种特定实施例中:
i)所述BRAFi为维罗非尼、达拉非尼、康奈非尼、LGX818、PLX4720、TAK-632、MLN2480、SB590885、XL281、BMS-908662、PLX3603、RO5185426、GSK2118436或RAF265,
ii)所述MEKi为AZD6244、曲美替尼、司美替尼(selumetinib)、考比替尼、贝美替尼(binimetinib)、MEK162、RO5126766、GDC-0623、PD 0325901、CI-1040、PD-035901、寄端霉素(hypothemycin)或TAK-733,
ⅲ)所述ERKi为尤仙替尼(ulixertinib)、去氢钩藤碱(corynoxeine)、SCH772984、XMD8-92、FR 180204、GDC-0994、ERK5-IN-1、DEL-22379、BIX 02189、ERK抑制剂(CAS编号1049738-54-6)、ERK抑制剂III(CAS编号331656-92-9)、GDC-0994、和厚朴酚(honokiol)、LY3214996、CC-90003、三角叶薯蓣皂苷(deltonin)、VRT752271、TIC10、黄芪甲苷IV(astragaloside IV)、XMD8-92、VX-11e、葫芦素(mogrol)或VTX11e,和/或
iv)所述EGFRi为西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、扎芦木单抗(zalutumumab)、尼妥珠单抗(nimotuzumab)、马妥珠单抗(matuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib)、拉帕替尼(lapatinib)、来那替尼(neratinib)、凡德他尼(vandetanib)、耐妥珠单抗(necitumumab)、奥希替尼(osimertinib)、阿法替尼(afatinib)、AP26113、EGFR抑制剂(CAS编号879127-07-8)、EGFR/ErbB-2/ErbB-4抑制剂(CAS编号881001-19-0)、EGFR/ErbB-2抑制剂(CAS编号179248-61-4)、EGFR抑制剂II(BIBX1382,CAS编号196612-93-8)、EGFR抑制剂III(CAS编号733009-42-2)、EGFR/ErbB-2/ErbB-4抑制剂II(CAS编号944341-54-2)或PKCβII/EGFR抑制剂(CAS编号145915-60-2)。
在本发明的特定实施例中,化学物质为免疫疗法试剂,更确切地说,免疫肿瘤学试剂,例如靶向CD52、PD-L1、CTLA4、CD20或PD-1的试剂。可与本发明化合物组合使用的试剂包含例如阿伦珠单抗(alemtuzumab)、阿特珠单抗(atezolizumab)、伊匹单抗、纳武单抗、奥法木单抗(ofatumumab)、派立珠单抗、利妥昔单抗(rituximab)。其它化学物质为例如阿法替尼(afatinib)、阿卡替尼(acalabrutinib)、阿莱替尼(alectinib)、阿帕替尼(apatinib)、阿西替尼(axitinib)、伯舒替尼(bosutinib)、卡博替尼(cabozantinib)、卡奈替尼(canertinib)、克诺拉尼(crenolanib)、西地尼布(cediranib)、克卓替尼(crizotinib)、丹拿堪索(damnacanthal)、达沙替尼(dasatinib)、恩脱替尼(entospletinib)、恩曲替尼(entrectinib)、埃罗替尼(erlotinib)、弗雷替尼(foretinib)、福他替尼(fostamatinib)、吉列替尼(gilteritinib)、格萨替尼(glesatinib)、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、伊马替尼(imatinib)、布立尼布(linafanib)、拉帕替尼(lapatinib)、来他替尼(lestaurtinib)、莫替沙尼(motesanib)、木利替尼(mubritinib)、尼达尼布(nintedanib)、尼罗替尼(nilotinib)、ONT-380、帕唑帕尼(pazopanib)、奎扎替尼(quizartinib)、瑞格非尼(regorafenib)、罗西替尼(rociletinib)、拉多替尼(radotinib)、沃利替尼(savolitinib)、西他伐替尼(sitravatinib)、司马沙尼(semaxanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、沃利替尼(savolitinib)、丝瓦替尼(sitravatinibg)、特撒替尼(tesevatinib)、凡塔蓝尼(vatalanib)、维罗非尼(vemurafenib)或凡德他尼(vandetanib)。
在另一实施例中,本发明涉及如本文所述的前述实施例中任一个的方法,其中一个或多个样品已经通过活检获得。
如本文所用,活检是涉及样品细胞或一个或多个组织的提取的医疗测试,通常进行活检来检查以测定疾病的存在或程度。组织一般在显微镜下由病理学家检查,和/或以化学方式分析。当去除整个肿块或可疑区域时,程序被称为切除活检。当仅去除组织样品并且保存组织细胞的组织学架构时,程序被称为切取活检或穿针活检(core biopsy)。当在去除细胞而不保持组织细胞的组织学架构的情况下用针去除组织或流体样品时,程序被称为针吸活检。除非另外规定,否则本发明中涵盖所有不同类型的活检。最常见地,为了理解可能的癌性和/或发炎性病状,确切地说,癌症,来进行活检。当疑似有癌症时,可应用所属领域的技术人员已知的多种活检技术。切除活检是去除整个病变的尝试。当评价样本时,除诊断之外,还检查病变周围未涉及的组织的量、样本的手术边界以查看疾病是否已扩散超出所活检区域。“干净边界”或“阴性边界”意指在活检样本的边缘处未发现疾病。“阳性边界”意指发现疾病,并且取决于诊断,可能需要更宽的切除。当出于多种原因不指示完整去除时,可以在切取活检中取得一块楔形组织。在本发明的一些实施例中,可以通过“咬住”样品的装置收集样品。多种尺寸的针可以收集管腔中的组织(穿针活检)。较小直径的针收集细胞和细胞簇,即细针吸活检。对活检体的病理检查可以测定病变是良性还是恶性的,并且可以帮助区分不同类型的癌症。与仅对病变进行取样的活检相比,病理学家,通常试图根除来自患者的已知病变的外科医生可能想到称为切除术(resection)的较大切除样本。举例来说,病理学家将检查乳房切除术样本,即使先前的非切除性乳房活检已经确立乳癌的诊断。完整乳房切除术样本的检查将确认癌症的确切性质(肿瘤的子分类和组织学“分级”)并且揭露其扩散程度(病理性“分期”)。在本发明的另一个实施例中,活检是液体活检,即,去除循环肿瘤细胞。此方法提供对重复侵入性活检的非侵入性替代方案以评价癌症中的突变并规划个性化治疗。此外,因为癌症为异质性遗传疾病,并且切除活检只提供肿瘤中发生的快速动态基因变化中的一些的即时快照,所以液体活检提供优于基于组织活检的基因组测试的一些优点。通过检测和定量CTC中的基因组变化,液体活检可提供关于肿瘤进展阶段、治疗有效性和癌转移风险的实时信息。在本发明的一个实施例中,因此设想使用液体活检。因此,在本发明的一个实施例中,使用活检从诊断患有癌症的个体获得待分析的样品。
术语“测定(determination)”或“测定(determining)”在本文中用于指代患者对特定化学物质(确切地说,治疗剂)产生抗性的风险的评价。在一个实施例中,测定(determination)或测定(determining)涉及那些抗性的程度。在一个实施例中,测定(determination)或测定(determining)涉及患者在治疗(例如用特定化学物质/治疗剂治疗)之后产生抗性的风险是否增加/降低。
本发明还涉及一种与额外化学物质组合用于治疗患者的癌症的化学物质,所述患者使用如本文中在各种实施例中所描述的本发明的方法测定为产生对所述化学物质的抗性,其中所述第二化学物质抑制与对于一种或多种第一化学物质产生癌症药物抗性相关的基因的表达。
在一个实施例中,本发明涉及一种或多种化学物质以及额外化学物质的用途,所述一种或多种化学物质用于治疗使用如本文中在各种实施例中所描述的本发明的方法测定为产生对所述化学物质的抗性的患者的癌症,所述额外化学物质抑制与对于一种或多种第一化学物质产生癌症药物抗性相关的一种或多种基因的表达。
本发明进一步包括一种产品,其含有一种或多种化学物质与额外化学物质的组合,所述一种或多种化学物质用于治疗使用如本文中在各种实施例中所描述的本发明的方法测定为诱发对所述化学物质的抗性的患者的癌症,所述额外化学物质抑制与对于第一化学物质产生癌症药物抗性相关的一种或多种基因的表达。
在一个实施例中,所述待治疗的癌症可为非黑素瘤皮肤癌、食管胃腺癌、成胶质细胞瘤、膀胱癌、膀胱尿道上皮癌、食管胃癌、黑素瘤、非小细胞肺癌、子宫内膜癌、宫颈腺癌、食管鳞状细胞癌、乳癌、头颈鳞状细胞癌、生殖细胞肿瘤、小细胞肺癌、卵巢癌、软组织肉瘤、肝细胞癌、结肠直肠腺癌、宫颈鳞状细胞癌、胆管癌、前列腺癌、上尿路尿道上皮癌、弥漫性神经胶质瘤、结肠直肠癌、壶腹癌、肾上腺皮质癌、头颈癌、肾透明细胞癌、肝胆癌、神经胶质瘤、非霍奇金淋巴瘤(non-Hodgkin lymphoma)、间皮瘤、唾液腺癌、肾非透明细胞癌、杂类神经上皮肿瘤、嗜铬细胞瘤、胸腺肿瘤、多发性骨髓瘤、肾细胞癌、骨癌、胰腺癌、白血病、周围神经系统肿瘤、甲状腺癌、B成淋巴细胞白血病、单克隆B细胞淋巴细胞增多、淋巴瘤、毛状细胞白血病、急性骨髓白血病、威尔姆斯肿瘤(Wilms tumor),尤其黑素瘤和非小细胞肺癌。以上疾病通常展现超过3%的以下的突变发生率:RTK(EGFR、ERBB2、ERBB3、ERBB4、PDGFA、PDGFB、PDGFRA、PDGFRB、KIT、FGF1、FGFR1、IGF1、IGFR、VEGFA、VEGFB、KDR)和/或MAPK路径成员(KRAS、HRAS、BRAF、RAF1、MAP3K1/2/3/4/5、MAP2K1/2/3/4/5、MAPK1/3/4/6/7/8/9/12/14、DAB、RASSF1、RAB25)。
用于本发明的化学物质可以是受体酪氨酸激酶(RTK)的抑制剂、EGFR路径的抑制剂(EGFRi)或MAPK路径的抑制剂(MAPKi),其中优选地,所述MAPKi为B-Raf的抑制剂(BRAFi)、MEK的抑制剂(MEKi)或ERK的抑制剂(ERKi)。在本发明的一个优选实施例中,化学物质可为BRAFi,确切地说,维罗非尼(vemurafenib)、达拉非尼(dabrafenib)、康奈非尼(encorafenib)、LGX818、PLX4720、TAK-632、MLN2480、SB590885、XL281或RAF265,和/或MEKi,确切地说,AZD6244、曲美替尼(trametinib)、司美替尼(selumetinib)、考比替尼(cobimetinib)、贝美替尼(binimetinib)、MEK162、RO5126766、GDC-0623、PD 0325901、CI-1040或TAK-733,和/或ERKi,确切地说,尤仙替尼(ulixertinib)、SCH772984、XMD8-92、FR180204、GDC-0994、ERK5-IN-1、DEL-22379、BIX 02189、ERK抑制剂(CAS编号1049738-54-6)、ERK抑制剂III(CAS编号331656-92-9)、GDC-0994或VTX11e,和/或EGFRi,确切地说,西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、扎芦木单抗(zalutumumab)、尼妥珠单抗(nimotuzumab)、马妥珠单抗(matuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib)、拉帕替尼(lapatinib)、AP26113、EGFR抑制剂(CAS编号879127-07-8)、EGFR/ErbB-2/ErbB-4抑制剂(CAS编号881001-19-0)、EGFR/ErbB-2抑制剂(CAS编号179248-61-4)、EGFR抑制剂II(BIBX 1382,CAS编号196612-93-8)、EGFR抑制剂III(CAS编号733009-42-2)、EGFR/ErbB-2/ErbB-4抑制剂II(CAS编号944341-54-2)或PKCβII/EGFR抑制剂(CAS编号145915-60-2)。
可以与第一化学物质同时或依序给予的第二化学物质抑制与产生癌症药物抗性相关的基因的表达。在优选实施例中,第二化学物质抑制选自由以下组成的群组的基因:SOX2、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。优选地,第二化学物质抑制SOX2的表达。
在这方面,本发明人意外且出乎意料地发现,现有的经过批准的药物可以用于抑制与抗药性相关的基因。因此,在本发明的一个优选实施例中,用于治疗癌症的化学物质(优选地,以上抑制剂中的一种)可以与现有的经过批准的药物组合,以便预防患者针对用于治疗癌症的化学物质产生抗药性。因此,在一个实施例中,本发明涉及用于治疗本发明的癌症的化学物质,其中第二化学物质选自由以下组成的群组:西曲溴铵(cetrimoniumbromide)、伊达比星盐酸盐(idarubicin·hcl)、来那替尼(neratinib)(hki-272)、异硫氰酸苯甲酯(benzyl isothiocyanate)、伏立诺他(vorinostat)、吐根素二盐酸盐(emetinedihydrochloride)、道诺霉素盐酸盐(daunorubicin hydrochloride)、更生霉素(dactinomycin)、奎西诺他(quisinostat)(jnj26481585)、氯硝柳胺(niclosamide)、小红莓(doxorubicin)、pci-24781(阿贝辛他(abexinostat))、毛花甙丙(lanatoside c)、帕比司他(panobinostat)(lbh589)、沙利霉素(salinomycin)钠、溴沙定(broxaldine)、替尼泊甙(teniposide)、浦西诺他(pracinostat)(sb939)、阿扎胞苷(azacitidine)、高三尖杉酯碱(homoharringtonine)、吖啶琐辛(acrisorcin)、氯化特洛尼姆(tolonium chloride)、拉多替尼(radotinib)、阿莫地喹二盐酸盐(amodiaquine dihydrochloride)、苄索氯铵(benzethonium chloride)、西达本胺(chidamide)、cudc-101、司拉克丁(selamectin)、汉防己碱(tetrandrine)、贝林诺他(belinostat)(pxd101)、依曲韦林(etravirine)(tmc125)、安西奈德(amcinonide)、奥苯达唑(oxibendazole)、乙酰基-l-亮氨酸(acetyl-l-leucine)、氯喔星(chloroxine)、纳布卡辛(napabucasin)、雷米诺他(resminostat)、碘苷(idoxuridine)、硫鸟嘌呤(tioguanine)、环己酰亚胺(cycloheximide)、曲氟尿苷(trifluridine)、17,21二丙酸倍他米松(betamethasone 17,21,dipropionate)、多韦替尼(dovitinib)(tki-258)二乳酸、秋水仙碱(colchicine)、莫塞诺他(mocetinostat)(mgcd0103)、舒尼替尼(sunitinib)、培利替尼(pelitinib)(ekb-569)、哌马色林(pimavanserin)、乙氧黄酮(efloxate)、tg101348(sar302503)、丙酸氯倍他索(clobetasolpropionate)、甲基泼尼松龙丁二酸钠(methylprednisolone sodium succinate)、乙酸二氯松(dichlorisone acetate)、阿苯达唑(albendazole)、恩替诺特(entinostat)(ms-275)、氟尼缩松(flunisolide)、青蒿醇(artenimol)、氨吖啶(aminacrine)、氟米松(flumethasone)、罗利诺他(rocilinostat)(acy-1215)、溴硝丙二醇(bronopol)、短杆菌肽(gramicidin)(所示为短杆菌肽a)、阿巴汀(abamectin)(所示为阿佛菌素b1a(avermectinb1a))、双硫仑(disulfiram)、二氟泼尼酯(difluprednate)、乙酰碘佐酸(acetriazoicacid)、乙酸异氟泼尼龙(isoflupredone acetate)、ly2835219、顺丁烯二酸哌克昔林(perhexiline maleate)、甲麦角林(metergoline)、福美司坦(formestane)、莫能菌素钠(monensin sodium)、氟尿苷(floxuridine)、泼尼卡酯(prednicarbate)、地塞米松磷酸钠(dexamethasone sodium phosphate)、来氟米特(leflunomide)、丙酸卤贝他索(halobetasol propionate)、西罗莫司(sirolimus)、依昔黄酮(ipriflavone)、尼达尼布(nintedanib)(bibf 1120)、扑蛲灵(pyrvinium)、双羟萘酸盐(pamoate)、芦氟沙星盐酸盐(rufloxacin hydrochloride)、福他布林(fosbretabulin)(磷酸考布他汀a4(combretastatin a4 phosphate,ca4p))二钠、二乙酸曲安西龙(triamcinolonediacetate)、奥太那班(otenabant)(cp-945598)盐酸盐、抑肽酶(aprotinin)、丙酸氟替卡松(fluticasone propionate)、阿姆瓦替尼(amuvatinib)(mp-470)、甲基苄索氯铵(methylbenzethonium chloride)、芬苯达唑(fenbendazole)、布比卡因盐酸盐(bupivacaine hydrochloride)、倍他米松(betamethasone)、特戊酸氟米松(flumethazonepivalate)、硫鸟嘌呤(thioguanine)、顺丁烯二酸替加色罗(tegaserod maleate)、泼尼松龙乙酸盐(prednisolone acetate)、二氢卟吩二酮(chlorindione)、半丁二酸氢皮质酮(hydrocortisone hemisuccinate)、乙酸地塞米松(dexamethasone acetate)、乙酸氟氢可的松(fludrocortisone acetate)、伊佛霉素(ivermectin)、半硫酸普鲁黄(proflavinehemisulfate)、兰索拉唑(lansoprazole)、赛度替尼(cerdulatinib)(prt062070,prt2070)、萨利方金(salifungin)、哈西奈德(halcinonide)、福多司坦(fudosteine)、特非那定(terfenadine)、醋酸氟轻松(fluocinonide)、海克替啶(hexetidine)、青蒿琥酯(artesunate)、氟轻松(fluocinolone acetonide)、利福平(rifampin)、曲安西龙(triamcinolone)、唑吡坦(zolpidem)、二乙丙苯嗪(ethopropazine)盐酸盐、瑞格非尼(regorafenib)(bay 73-4506)、特拉唑嗪盐酸盐(terazosin hydrochloride)、丹参酮iia-磺酸钠(tanshinone iia-sulfonic sodium)、诺考达唑(nocodazole)、三氯生(triclosan)、氯羟吡啶(clopidol)、甲苯磺酸索拉非尼(sorafenib tosylate)、磺胺二甲异嘧啶(sulfisomidine)、亚甲基蓝(methylene blue)、克卓替尼(crizotinib)(pf-02341066)、海葱次甙a(proscillaridin a)、右布洛芬(dexibuprofen)、三氟丙嗪盐酸盐(triflupromazine hydrochloride)、吡贝地尔盐酸盐(piribedil hydrochloride)、卡莫氟(carmofur)、獐牙菜苦苷(swertiamarin)、甲苯磺酸舒它西林(sultamicillintosylate)、人参皂苷rc(ginsenoside rc)、依托贝特(etofibrate)、氯化十六烷基吡锭(cetylpyridinium chloride)、雷贝拉唑钠(rabeprazole sodium)、阿立必利盐酸盐(alizapride hydrochloride)、氨基乙酰丙酸甲酯·盐酸盐(methyl aminolevulinate·hcl)、托匹司他(topiroxostat)、四水合氯屈膦酸二钠(disodium clodronatetetrahydrate)、阿莫沙平(amoxapine)、贝达喹啉(bedaquiline)(tmc207;r207910)、奥替尼啶(octenidine)、依卡倍特钠(ecabet sodium)、芹黄素(apigenin)、格隆溴铵碘(glycopyrrolate iodide)、蒙脱石钠(sodium montmorillonite)、氢皮质酮(hydrocortisone)。设想作为与抗药性相关的基因的抑制剂的其它化学物质包含靶向以下的物质:ARRB1、ATXN7L3、CBX1、CREBBP、CTBP2、CUL3、DDB2、FMR1、FOXO1、KDM4B、KMT2E/MLL5、NIPBL、OGFOD1、RBX1、SF3B1、SFPQ、SRSF1、SSRP1、YWHAZ或ZMYND11;例如巴巴丁(barbadin)、CCS1477、SGC-CBP30、CPI-637、PF-CBP1、ICG,001,PRI-724、A-485、C646、4-甲硫基-2-氧代丁酸(MTOB)、HIPP衍生物、环肽CP61、NSC95397、2-(羟亚氨基)-3-苯基丙酸和其4-氯和3-氯类似物、MLN4924、AS1842856、JIB-04、EP-5676、N-草酰甘氨酸(NOG)、吡啶-2,4-二甲酸酯(2,4-PDCA)、普拉地内酯B(pladineolide B)、IDC16、CBL0137、迪福平(difopein)或R18。
本发明还涵盖图式中个别地展示的所有其它特征,但其可能未在先前或以下描述中描述。并且,可在本发明的另一方面的标的物中不要求图式和描述中描述的实施例的单一替代方案及其特征的单一替代方案。
此外,在权利要求书中,词语“包括”不排除其它要素或步骤,并且不定冠词“一(a)”或“一(an)”不排除多个。一个单元可满足权利要求书中所叙述的若干特征的功能。结合属性或值的术语“基本上”、“约”、“大致”等,确切地说,也分别确切定义所述属性或确切定义所述值。权利要求书中的任何参考标记不应解释为限制范围。
如本说明书和所附权利要求书中所使用,除非上下文另外明确规定,否则单数形式“一(a)”、“一(an)”和“所述”包含多个指示物。因此,举例来说,提及“一化合物”包含一种或多种化合物。
术语“治疗(treatment)”、“治疗(treating)”等在本文中用于一般意味获得所需药理学和/或生理作用。作用可在完全或部分地预防疾病或其症状方面为预防性的,和/或可在部分或完全地治愈疾病和/或归因于疾病的不良影响方面为治疗性的。如本文所用,术语“治疗”涵盖个体疾病的任何治疗并且包含:(a)预防疾病;(b)抑制疾病,即遏制其发展;或(c)缓解疾病,即引起疾病消退。
出于本发明的目的,“患者”或“个体”可互换地使用且意图包含人类和其它动物,确切地说,哺乳动物,和其它生物体。因此,所述方法适用于人类疗法和兽医学应用两者。在优选实施例中,患者或个体为哺乳动物,并且在最优选实施例中,患者或个体为人类。
基于细胞的筛选方法可以用于鉴别有效治疗特征在于由过度活化的信号传导路径表征的细胞的癌症的化合物,所述化合物与所述信号传导路径的抑制剂一起呈组合药剂形式,所述方法包括以下步骤:a)提供在编码包括于所述信号传导路径中的蛋白质的基因中携带活化突变或扩增的细胞;b)使所述细胞与所述信号传导路径的抑制剂;以及测试化合物接触;c)测定选自由以下组成的群组的与产生抗性相关的基因的表达量:SOX2、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。优选地,第二化学物质抑制SOX2的表达;和d)向所述测试化合物指配评分,其中如果SOX2和/或与产生抗性相关的另一基因的所述表达量低于预定阈值,那么所述评分为高的,所述阈值对应于单独用所述信号传导路径的所述抑制剂处理的对照组细胞中SOX2和/或与产生抗性相关的另一基因的表达量;如果SOX2和/或与产生抗性相关的另一基因的所述表达量等于或高于所述预定阈值,那么所述评分为低的。
可以在步骤a)中同时采用多个细胞;所述多个细胞一起提交到步骤b);测定所述多个细胞的SOX2和/或与产生抗性相关的另一基因的平均表达量;且如果所述SOX2和/或与产生抗性相关的另一基因的平均表达量低于单独用所述信号传导路径的所述抑制剂处理的对照组细胞中SOX2和/或与产生抗性相关的另一基因的平均表达量,那么向所述测试化合物指配高评分。
确切地说,可在步骤a)中同时采用多个细胞;所述多个细胞一起提交到步骤b);如果所述SOX2表达量和/或与产生抗性相关的另一基因高于针对未处理细胞测定的表达量,那么将单一细胞评价为“SOX2阳性”,且针对所述多个细胞测定“SOX2阳性”细胞与总细胞的比率;和d)如果针对用所述测试化合物处理的细胞所测定的所述比率低于针对仅用所述信号传导路径的抑制剂处理的对照组细胞所测定的所述比率,那么向所述测试化合物指配高评分。
技术人员熟知适合于测定SOX2和/或与产生抗性相关的另一基因的表达量的方法。在一个特定实施例中,通过分析蛋白质表达和/或mRNA表达来测定表达量。然而,可以在本发明中采用使用来源于基因组、转录组和/或蛋白质组的信息的任何方法。举例来说,表达量可以(SOX2和/或与产生抗性相关的另一基因的)蛋白质含量测定,且可通过使用标记(确切地说,抗体介导的染色)直接观测和定量。还可以通过使用原位杂交直接观测来以(SOX2和/或与产生抗性相关的另一基因)mRNA含量测定表达量。使用此类技术,可以对个别分子进行定量。
在某些实施例中,与产生抗性相关的基因选自包括以下的群组:Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
因此,在本发明内,可以使用所属领域中已知的任何技术,例如基于聚核苷酸(mRNA转录物)的杂交的方法、基于聚核苷酸测序或聚核苷酸扩增的方法来测定基因表达量。
可以使用(但不限于)RNA印迹法(northern blotting)、原位杂交、RNA酶蛋白酶分析、基于PCR的方法(如逆转录聚合酶链反应(RT-PCR)和实时定量PCT qRT-PCR)进行样品中mRNA基因转录物的定量。或者,具有对核酸双螺旋体的结合特异性的抗体可以用于测定mRNA含量。可以用使用相关RNA的特异性结合成员的微阵列技术,所述特异性结合成员例如对相关RNA具有特异性的cDNA或寡核苷酸探针,或对相关mRNA具有特异性的抗体,其中特异性结合成员涂铺或排列在底物上,所述底物例如载玻片或微芯片底物。特异性结合成员可在可寻址位置处提供于底物上,且可寻址位置的数目可在例如至少三个、至少10个、至少50个、至少100个、至少1000个或至少10,000个或更多的范围内变化。在实施例中,可寻址位置的数目可在小于1000个、小于100个、小于50个、小于10个或小于5个的范围内变化。在此类实施例中,使样品与阵列接触,并且经过排列的特异性结合成员可与样品中的靶形成可检测的相互作用。可使用适合的标记检测相互作用。在利用寡核苷酸探针的情况下,在适当条件下,寡核苷酸探针可“杂交”到靶核酸序列以与具有互补碱基序列的核酸分子形成碱基配对双螺旋体。产生特定程度的严格度的杂交条件将取决于杂交方法的性质和杂交核酸序列的组成和长度而变化。
当核酸以最少背景结合靶核酸时,发生严格杂交。通常,为了实现严格杂交,使用低于Tm(一半分子从其搭配物解离的解链温度)的约1℃到约20℃,更优选地,5℃到约20℃的温度。然而,其进一步由溶液的离子强度和pH值定义。适合杂交条件将为所属领域的技术人员已知,并且示范性杂交条件为:极高严格度(检测共有至少90%一致性的序列)-在65℃下杂交5×SSC约16小时、高严格度(检测共有至少80%一致性的序列)-在65℃下杂交5×-6×SSC16小时,以及低严格度(检测共有至少50%一致性的序列)-在室温到55℃下杂交6×SSC 20到30分钟。
高度严格洗涤条件的实例为在72℃下,0.15M NaCl,持续约15分钟。严格洗涤条件的实例为在65℃下,0.2×氯化钠和柠檬酸钠(SSC)洗涤15分钟(关于SSC缓冲液的描述,参见下文的Sambrook和Russell,例如通过将175.3gNaCl和88.9g柠檬酸钠溶解于800ml蒸馏水中制备的20×SSC。用HCI(IM)调节pH值到pH 7.0并且用蒸馏水调节体积到IL)。通常,在高严格度洗涤之前进行低严格度洗涤以去除背景探针信号。例如大于100个核苷酸的双螺旋体的中严格度洗涤的实例为在45℃下,1×SSC,持续15分钟。例如大于100个核苷酸的双螺旋体的低严格度洗涤的实例为在40℃下,4-6×SSC,持续15分钟。对于短探针(例如约10到50个核苷酸),严格条件通常涉及小于约1.5M的盐浓度,更优选在pH 7.0到8.3下约0.01到1.0M的Na离子浓度(或其它盐),并且对于长探针(例如>50个核苷酸),温度通常为至少约30℃和至少约60℃。
用于PCR方法(例如RT-PCR和PCT和RT-PCR)中的方法论对于所属领域的技术人员将是熟知的。
一些方法可能需要从样品中分离RNA。此类分离技术为所属领域中已知的,并且可利用来自制造商(如Qiagen)的市售RNA分离试剂盒。
蛋白质表达免疫组织化学(IHC)的测定和ELISA是适用于检测蛋白质表达的技术。抗体或抗体的结合片段(单克隆或多克隆)可以用于所公开的方法和试剂盒中。抗体可以通过直接标记抗体或通过使用对具有对靶的结合特异性的初级抗体具有特异性的第二抗体来检测。第二抗体可以用可检测部分标记或可以与半抗原(如生物素等)结合,其中半抗原可以通过可检测标记的同源半抗原结合分子,例如抗生蛋白链菌素辣根过氧化酶(streptavidin horseradish peroxidise)检测。
抗体(对特定抗原,例如SOX2和/或与产生抗性相关的另一基因具有结合特异性的抗体)的结合特异性可以使用蛋白质印迹法(Western blotting),与模拟原发性肿瘤的处理的福尔马林固定、石蜡包埋的细胞系的免疫组织化学分析并行地建立(如O'Brien等人,2007,《癌症国际杂志(International Journal of Cancer)》,120:1434-1443描述)。
或者,蛋白质可以使用以下来检测:适配体(例如采用特定序列依赖型形状并且以高亲和力和特异性结合到FKBPL蛋白质的单股核酸分子(如DNA或RNA))、镜像适配体(SPIEGELMERTM)、工程改造的非免疫球蛋白结合蛋白,例如基于包含纤维结合蛋白(ADNECTINSTM)、CTLA-1(EVIBODIESTM)、脂笼蛋白(ANTICALINSTM)、蛋白质A域(AFFIBODIESTM)等的骨架的非免疫球蛋白结合蛋白。在实施例中,适配体可包括小于100个核苷酸、小于75个核苷酸、小于50个核苷酸、例如25到50个核苷酸、10到50个核苷酸、10到100个核苷酸。
在特定实施例中,可以提供包括蛋白质序列的阵列,所述蛋白质序列包含SOX2蛋白质或SOX2蛋白质的片段或对SOX2蛋白质或其片段具有结合特异性的抗体。这些蛋白质序列或抗体可以与底物结合。蛋白质表达的改变可以通过例如测量样品中SOX2蛋白质和/或与产生抗性相关的另一基因(其在待测试样品与阵列接触时,结合到对SOX2蛋白质和/或与产生抗性相关的另一基因具有结合特异性的抗体)的含量来检测。
在某些实施例中,与产生抗性相关的基因选自包括以下的群组:Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
以阵列和阵列格式使用的适合底物将为所属领域的技术人员已知的。
在特定实施例中,可使用自动化图像分析系统分析IHC样品,以便提供盲目分析(blinded analysis)。对此,可首先使用ScanScope XT玻片扫描仪(Aperio Technologies)以20×捕获整个玻片的数字图像。其次,正像素计数算法(Aperio Technologies)可用于开发用于SOX2表达的定量评分模型。组织微阵列来源的数据的统计分析可使用v2趋势测试(v2 test for trend)、费舍尔精确检验(Fisher's exact)和曼-惠特尼测试(Mann-Whitney test)来进行,以用于比较SOX2表达,且卡普兰-迈耶曲线(Kaplan-Meier plot)可用于存活率分析,且使用对数秩测试来比较曲线。考克斯比例风险回归(Cox proportionalhazards regression)可用于估计比例风险比率且如先前所描述进行多变量分析。可以用SPSS第11.0版(伊利诺伊州,SPSS(SPSS,IL))执行所有计算。此外,为了促进生成离散多标记物测试,可以同时使用荧光标记的抗体(携带不重叠荧光团)以及额外的相关生物标记物。有利地,可使用来自Aperio的最近开发的荧光扫描系统,例如ScanScope FL系统。此分析方法将通过提供比由常规亮场成像所获得的更多的定量分析来提供另一层复杂度。如将了解,检测SOX2的表达、SOX2在细胞中的位置或SOX2的活性的方法可适用于本文中所描述或要求的本发明的方法中的任一个。
除非上下文另外要求,否则本发明的每一方面的优选特征和实施例相对于其它方面中的每一个加以必要更改。
如果两个分子共有大量互补核苷酸以在股彼此结合(杂交)(例如通过形成沃森-克里克碱基对(Watson-Crick base pair))时形成稳定双螺旋体或三螺旋体,那么称核酸分子与另一核酸分子互补。互补性可以描述为两个核酸分子的特定区域内两个分子之间的碱基对的比例的百分比。
接触意指使试剂与另一试剂极为接近,使得两种试剂可彼此相互作用。举例来说,抗体或其它结合成员可以与样品中的蛋白质极为接近,并且其中当抗体对蛋白质具有结合特异性时,抗体将结合蛋白质。或者,可以使第一核酸与第二互补核酸(具有靶序列的引物)极为接近并且可以进行培育,使得可以检测到结合或可以发生靶序列的扩增。
检测意指测定两种试剂(例如两种蛋白质或两种核酸)之间的相互作用存在还是不存在。这可包含定量。检测可以包含使用例如使用分光光度法、流式细胞测量术或显微法能够进行检测的试剂(标记)。示范性标记包含放射性同位素(如3H、14C、15N、35S、90V、99Tc、111Ln、125I1或131I)、荧光团(如荧光素、异硫氰酸荧光素、若丹明(rhodamine)等)、发色团、配体、化学发光剂、生物发光剂(如荧光素酶、绿色荧光蛋白(GFP)或黄色荧光蛋白)、可产生可检测反应产物的酶(如辣根过氧化酶、荧光素酶、碱性磷酸酶、β-半乳糖苷酶)和其组合。
特异性结合意指一结合搭配物与另一结合搭配物,例如引物与靶序列或蛋白质特异性抗体与蛋白质之间的特异性相互作用。一结合搭配物与另一结合搭配物之间的相互作用可以由一个或多个,通常多于一个非共价键介导。表征特异性结合的示范性方式为通过特异性结合曲线。
在本发明的方法的另一实施例中,方法包括如下步骤:其中在用所述信号传导路径的所述抑制剂和所述测试化合物处理的所述细胞中,测定细胞周期阶段,确切地说,检测细胞周期停滞,并且其中如果所述细胞经历细胞周期停滞,那么向所述测试化合物指配高评分。
在本发明的方法的特定实施例中,信号传导路径为MAPK或EGFR路径。在本发明的这个实施例中,癌症的特征可以在于在编码包括于MAPK或EGFR路径中的蛋白质的基因中携带活化突变或扩增(确切地说,NRAS、KRAS、HRAS、BRAF、MEK、ERK、ROS、ALK、MET、KIT或EGFR中的活化突变或扩增)的癌细胞。癌症然后可以选自非黑素瘤皮肤癌、食管胃腺癌、成胶质细胞瘤、膀胱癌、膀胱尿道上皮癌、食管胃癌、黑素瘤、非小细胞肺癌、子宫内膜癌、宫颈腺癌、食管鳞状细胞癌、乳癌、头颈鳞状细胞癌、生殖细胞肿瘤、小细胞肺癌、卵巢癌、软组织肉瘤、肝细胞癌、结肠直肠腺癌、宫颈鳞状细胞癌、胆管癌、前列腺癌、上尿路尿道上皮癌、弥漫性神经胶质瘤、结肠直肠癌、壶腹癌、肾上腺皮质癌、头颈癌、肾透明细胞癌、肝胆癌、神经胶质瘤、非霍奇金淋巴瘤、间皮瘤、唾液腺癌、肾非透明细胞癌、杂类神经上皮肿瘤、嗜铬细胞瘤、胸腺肿瘤、多发性骨髓瘤、肾细胞癌、骨癌、胰腺癌、白血病、周围神经系统肿瘤、甲状腺癌、B成淋巴细胞白血病、单克隆B细胞淋巴细胞增多、淋巴瘤、毛状细胞白血病、急性骨髓白血病、威尔姆斯肿瘤,尤其黑素瘤和非小细胞肺癌。在本发明的方法的特定实施例中,步骤a中所提供的细胞选自携带BRAF突变,确切地说,BRAF-V600E或BRAF-V600K突变的黑素瘤细胞或非小细胞肺癌细胞,和携带EGFR突变、扩增或过度表达的非小细胞肺癌细胞。
在本发明的方法中,信号传导路径的抑制剂可以例如选自EGFR路径的抑制剂(EGFRi)和MAPK路径的抑制剂(MAPKi),其中确切地说,所述MAPKi选自B-Raf的抑制剂(BRAFi)、MEK的抑制剂(MEKi)和ERK的抑制剂(ERKi)。在本发明中,此类抑制剂可为维罗非尼、达拉非尼、康奈非尼、LGX818、PLX4720、TAK-632、MLN2480、SB590885、XL281或RAF265,所述MEKi可为AZD6244、曲美替尼、司美替尼、考比替尼、贝美替尼、MEK162、RO5126766、GDC-0623、PD 0325901、CI-1040或TAK-733,所述ERKi可为尤仙替尼、SCH772984、XMD8-92、FR180204、GDC-0994、ERK5-IN-1、DEL-22379、BIX 02189、ERK抑制剂(CAS编号1049738-54-6)、ERK抑制剂III(CAS编号331656-92-9)、GDC-0994或VTX11e,或所述EGFRi可为西妥昔单抗、帕尼单抗、扎芦木单抗、尼妥珠单抗、马妥珠单抗、吉非替尼、埃罗替尼、拉帕替尼、AP26113、EGFR抑制剂(CAS编号879127-07-8)、EGFR/ErbB-2/ErbB-4抑制剂(CAS编号881001-19-0)、EGFR/ErbB-2抑制剂(CAS编号179248-61-4)、EGFR抑制剂II(BIBX 1382,CAS编号196612-93-8)、EGFR抑制剂III(CAS编号733009-42-2)、EGFR/ErbB-2/ErbB-4抑制剂II(CAS编号944341-54-2)或PKCβII/EGFR抑制剂(CAS编号145915-60-2)。
在本发明的情形下,并且确切地说,本发明的方法的情形下,术语“包括于信号传导路径中的蛋白质”涉及在细胞中相互作用以控制特定细胞功能,如增殖、分化或细胞凋亡的分子。包括于一个信号传导路径中的分子为协同活化级联的一部分。在刺激下,路径中的第一分子活化一个或若干个下游分子。活化继续传递,直到活化链中的最后一个分子活化并且进行细胞功能。关于MAPK路径,这涉及选自包括以下的群组的特定配体、受体和下游转录因子:NGF、NRG、BDNF、NT3/4、EGF、FGF、PDGF、CACN、TrkA/B、EGFR、FGFR、PDGFR、ROS、ALK、MET、KIT、GFB2、SOS、HRAS、KRAS、NRAS、RasGRF、RasGRP、CNasGEF、PKC、PKA、Rap1、G12、Gap1m、NF1、p120GAF、RafB、ARAF、BRAF、CRAF、Mos、MEK1、MEK2、MP1、ERK1、ERK2、PTP、MKP、Tau、STMN1、cPLA2、MNK1/2、RSK2、CREB、Elk-1、Sap1a、c-Myc、SRF5和c-fos。
在本发明的情形下,术语“活化突变”涉及引起基因产物的活性增加的基因的核苷酸序列的改变。活性增加可归因于增强的酶活性、延长的半衰期或基因产物的过度表达。
在本发明的情形下,术语“在SOX2的转录控制下的基因”涉及特征在于在SOX2不在相同细胞中表达的情况下的第一表达量,和在SOX2在相同细胞中表达的情况下的第二表达量的基因。第一表达量低于第二表达量。在某些实施例中,与产生抗性相关的基因选自包括以下的群组:Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
在某些实施例中,本发明提供一种基于细胞的方法,其测定癌症患者中,患者是否处于产生对有效治疗癌症的化学物质或化合物的抗性的风险下。癌症的特征在于由过度活化的信号传导路径表征的细胞。过度活化可以由编码在信号传导路径中起作用的蛋白质的基因的活化突变或扩增引起。技术人员应了解,信号传导路径的过度活化还可能由编码信号传导路径的抑制剂的基因(如NF1)的抑制突变或缺失引起。化合物在包括相应过度活化的信号传导路径的抑制剂的组合药剂中有效治疗癌症。
在这方面,本发明人意外地发现突变型BRAF和MEK的抑制剂(下文统称为MAPK抑制剂,MAPKi)在施用药物的数小时内诱发黑素瘤细胞中的急性转录反应(即,适应性抗药性程序;ARP)。这些ARP涉及SOX2依赖型干细胞性(stemness)、轴突导向(axon guidance)和上皮细胞向间叶细胞转化(epithelial-to-mesenchymal transition,EMT)基因的转录诱导,使得产生耐药性细胞的池(图1)。从长远观点来看,这些耐药性细胞可以作为产生获得性抗性的种源。耐药性细胞的数目可以通过SOX2(干细胞性的主调节因子和MAPKi诱导ARP的主驱动因子)的siRNA介导的基因敲除而显著减少(图2)。因此,在临床情形中通过钝化MAPKi诱导的SOX2来防止诱导ARP将具有预防获得性抗药性,因此延长临床使用的MAPK抑制剂的耐久性的最高治疗价值。
除非另外定义,否则本文中所使用的所有技术和科学术语都具有与本发明所涉及的领域的一般技术人员通常所理解相同的含义。尽管可在本发明的实践或测试中使用与本文中所描述的方法和材料类似或等效的方法和材料,但下文描述适合的方法和材料。在矛盾的情况下,将以本说明书,包含定义为准。另外,材料、方法和实例仅为说明性的且并不意图为限制性的。
借助于以下说明性非限制性实例额外描述本发明的各方面,所述说明性非限制性实例提供对本发明的实施例和其许多优点的更好的理解。包含以下实例以展现本发明的优选实施例。所属领域的技术人员应了解,以下实例中所公开的技术表示在本发明的实践中良好地起作用的本发明中所使用的技术,且因此可被视为构成其实践的优选模式。然而,根据本公开,所属领域的技术人员应了解,在不脱离本发明的精神和范围的情况下,可对所公开的特定实施例作出许多改变,且仍获得相似或类似结果。
除非另外指示,否则如例如以下中所描述使用重组基因技术的确立方法:Sambrook,Russell《分子克隆实验指南(Molecular Cloning,A Laboratory Manual)》,冷泉港实验室(Cold Spring Harbor Laboratory),纽约(2001),其以全文引用的方式并入本文中。
本文中引用许多文献,包含专利申请、制造商手册和科学出版物。这些文献的公开内容虽然不被视为与本发明的专利性相关,但其全部内容以引用的方式并入本文中。更确切地说,所有所参考的文献以引用的方式并入,其引用程度如同特定地并且个别地指示每一个别文献以引用的方式并入一般。
附图说明
图1展示了通过RNA测序(RNA-Seq)分析的用MAPKi进行急性处理时干细胞性和EMT标签的诱导。(A)用PLX4720(BRAFi)或DMSO处理A375-P细胞6小时,分离RNA并且进行RNA测序。散布图展示具有≥0.5RPKM的最小标准化丰度的所有基因。被选择进行路径分析的差异表达的基因(DEG)取决于转录改变的方向由红点和蓝点表示(红色基因在PLX4720下诱导,蓝色基因在PLX4720下抑制)。(B)条形图展示所分析的DEG富集最显著的前五个路径。较长条指示更显著。(C)用PLX4720处理时失调最显著的基因(左列)。受PLX4720诱导和抑制最显著的基因展示于分开的列表中。(D)用1μM PLX4720或0.01%DMSO(0h)处理指示细胞系持续指示时间,并且通过qPCR确认与干细胞性/EMT相关的所选基因的表达变化。所有细胞系在BRAF抑制下表达类似的适应性基因程序。展示的数据表示一式三份独立生物样品的平均值±SEM。(E)如(D)中所示的相同实验的蛋白质印迹分析。作为干细胞性标签中的关键作用因素,评估SOX2含量。P-ERK1/2含量充当阳性处理对照组。总ERK1/2含量充当内对照组(loading control)。(F)用1μM PLX4720、0.5μM AZD6244(MEK1/2抑制剂)或0.01%DMSO处理A375-P细胞持续指示时间,并且通过蛋白质印迹分析评估SOX2含量。应注意,BRAF的抑制和MEK1/2的抑制诱导类似SOX2含量,表明这是致癌MAPK抑制的一般特征。(G)用1μMPLX4720(BRAFi)、0.5μM AZD6244(MEKi)、两种药物的组合或0.01%DMSO处理A375-P细胞持续指示时间,并且通过蛋白质印迹分析评估SOX2含量。应注意,BRAFi和MEKi对SOX2含量具有相当的影响,并且两种药物的组合产生稍微更高的SOX2含量。(H)用1μM PLX4720(BRAFi)、0.5μM AZD6244(MEKi)、两种药物的组合或0.01%DMSO处理A375-P细胞24小时,并且通过qPCR确认与干细胞性/EMT相关的所选基因的表达变化。应注意,BRAFi和MEKi对转录水平具有相当的影响,并且两种药物的组合对转录诱导稍微更有效。对于所有蛋白质印迹,在至少两个独立实验中评估个别时间点。展示代表性数据。
图2展示SOX2针对MAPKi诱导的抗增殖作用的保护性作用。(A)用靶向SOX2的100nMsiRNA或阴性对照组siRNA转染A375-P细胞。细胞接着用PLX4720(BRAFi)或DMSO处理48小时。在收集前2小时,细胞用3μM EdU脉冲以标记循环细胞。使用流式细胞测量术检测EdU阳性细胞。应注意,当BRAF具有活性时(DMSO),SOX2基因敲除对细胞增殖没有影响,但减少BRAFi条件下的耐药性循环细胞的池。展示代表性数据。(B)实验(A)的定量。对于每一条件,将在SOX2的siRNA基因敲除下的循环细胞百分比标准化到阴性对照组siRNA。展示的数据表示一式三份独立生物样品的平均值±SEM。(C)用指示浓度的多西环素(doxycycline)处理用pTRIPZ-SOX2载体稳定转导的A375-P细胞三天或用1μM PLX4720(PLX)处理24小时。通过蛋白质印迹分析确认SOX2过度表达。核纤层蛋白A(Lamin A)充当内对照组。在至少两个独立实验中评估个别浓度。展示代表性结果。(D)用0ng/ml(阴性对照组)或用50ng/ml多西环素预处理A375-P/pTRIPZ-对照组细胞或A375-P/pTRIPZ-SOX2细胞24小时,并且随后用DMSO或PLX4720再处理48小时。在收集前2小时,细胞用3μM EdU脉冲以标记循环细胞。使用流式细胞测量术检测EdU阳性细胞。将展示的数据标准化到在无多西环素条件下循环细胞的百分比。展示为一式三份独立生物样品的平均值±SEM。(E)用0ng/ml(阴性对照组)或用50ng/ml多西环素预处理A375-P/pTRIPZ-对照组细胞或A375-P/pTRIPZ-SOX2细胞24小时,并且随后用PLX4720的连续稀释液再处理四天。通过PrestoBlue分析评估细胞存活率并且计算IC50值。应注意多西环素对pTRIPZ-对照组细胞没有影响,但使得pTRIPZ-SOX2细胞的存活率曲线向右偏移,指示当SOX2过度表达时药物敏感性下降。在存活率曲线之上陈述IC50值。将展示的数据标准化到DMSO处理的细胞。误差条指示三个独立实验的SEM。(F)用0ng/ml(阴性对照组)或用50ng/ml多西环素预处理A375-P/pTRIPZ-对照组细胞或A375-P/pTRIPZ-SOX2细胞24小时,并且随后用DMSO或PLX4720再处理48小时。通过蛋白质印迹评估存活信号传导。经由S6K和BAD的存活信号传导由PLX4720抑制,但当SOX2通过多西环素处理过度表达时恢复。
图3化合物孔分配的热图表示。阴性:DMSO;阳性:5μM恩替诺特;c:5μM测试化合物;r1:1μM恩替诺特;r3:3μM恩替诺特;r10:10μM恩替诺特。
图4展示原始荧光fl2和fl3以及其比率y的对照组孔的对数变换信号。y轴在1%与99%分位数之间按比例缩放。
图5标准化(norm)之前(y)和之后的对照组孔的对数变换信号。y轴在1%与99%分位数之间按比例缩放。
图6前4个板的相对于列数或行数的原始信号。如果存在,那么可鉴别整体行或列效果。
图7前4个板的相对于行数(A,C)或列数(B,D)的标准化(A,B)和几何校正信号(C,D)。整体行或列效果应不再可见。
图8对照组和化合物的分布。(A)经验概率密度,(B)分位数-分位数曲线,(C)逐板MAD相对于逐板中值。(D)P值分布(PVD)。常规PVD可具有2个不同形状:(i)不存在DEG的情况下,均一(密度=1的平线区)。(ii)较小p值下的峰和对于p->1的平线区<1;平线区值对应于DEG比例。任何其它形状都是不规则的,并且敏感地指示对模型假设的违反。
图9所有孔的火山图显示测试的显著性之间的关系,表示为错误发现率(FDR)的负对数,以及效果量,表示为倍数变化的对数。水平线对应于FDR=0.01,且此线下方的化合物标记为‘不显著’。两条垂直线对应于活性的0.5改变,且此范围外的化合物标记为‘强’。
具体实施方式
实例1-用于测定抗性产生的方法
1.肿瘤切片的制备和离体处理
在加工之前,将过剩的肿瘤组织在4℃下在冷无血清RPMI 1620格鲁塔玛(Glutamax)中储存长达24小时。将大活检体修整到约1cm最大直径。
在40ml标记处切割50ml法尔康管(Falcon tube)并且丢弃底部部分。将活检体放入缩短的法尔康管的盖子中。用液体4%低温琼脂糖(SeaPlaque琼脂糖,龙沙(Lonza))填充管直到45ml标记。使琼脂糖在冰上固化。
一旦固化,从法尔康管中移出琼脂糖块并且将其修整成矩形。在组织活检体的左边和右边留下约2mm琼脂糖。在组织活检体的顶部和底部留下约5mm琼脂糖以防止在切割程序期间组织被推出琼脂糖。
使用氰基丙烯酸酯粘合剂将经过修整的琼脂糖块胶合到振荡切片机(徕卡VT1000S振动刀薄片切片机(Leica VT1000 S Vibrating blade microtome))的样本固持器上,并且使其在室温下干燥。一旦干燥,就将样本固持器扣入到缓冲托盘中,且缓冲托盘安装在冰浴托盘中。缓冲托盘填充有冰冷PBS。以约0.30mm/s的速度和约0.70mm的振动幅度将活检体切割成400μm厚的切片。
向6孔板的每个孔中添加1ml含有1×抗生物剂-抗霉菌剂(Gibco)和10%FCS的PRMP 1620格鲁塔玛。将一个Millicell插入物(Millicell细胞培养插入物,30mm,亲水性PTFE,0.4μm)转移到每个孔中。将若干切片转移到一个Millicell插入物上。将切片保持于加湿的细胞培养箱(21%O2,5%CO2)中,且使其恢复24小时。
在恢复之后,通过将Millicell插入物转移到含有1ml PRMP 1620格鲁塔玛(1×抗生物剂-抗霉菌剂(Gibco),10%FCS)和0.01%DMSO(用于对照组活检体)或0.5μM司美替尼(用于处理组活检体)的6孔板上的孔中来冲洗Millicell插入物。
然后将插入物转移到含有1ml PRMP 1620格鲁塔玛(1×抗生物剂-抗霉菌剂(Gibco),10%FCS)和0.01%DMSO(用于对照组活检体)或0.5μM司美替尼(用于处理组活检体)的新孔中。将活检体在加湿的细胞培养箱中培育16小时到48小时。
2.肿瘤切片的基因表达分析
为了分析基因表达,使用无菌镊子将肿瘤切片转移到2.0ml埃彭道夫安全锁微量离心管(Eppendorf Safe-Lock microcentrifuge tube)(圆底)中,称重,在液氮中快速冷冻并且在-80℃下储存直到进一步使用。根据制造商说明书取决于组织重量使用RNeasy迷你或微型试剂盒(Qiagen)分离RNA,并且在10-30μl无RNA酶水中洗脱并且在-80℃下储存。使用NanoDrop 2000(Thermo Scientific)以分光光度法测定RNA浓度和纯度。根据制造商说明书使用大容量cDNA逆转录试剂盒(Thermo Fisher Scientific)将RNA逆转录到cDNA。每20μl反应物,在罗氏(Roche)LightCycler 480多孔板中制备以下混合物:3μl水、1μl 5μM正向引物、1μl 5μM反向引物、10μl LightCycler 480SYBR Green I Master(2×)或KAPAFAST qPCR试剂盒、5μl cDNA[5ng/μl]。将样品一式两份地移液。96孔板在2000rpm下离心1分钟且在LightCylcer 480装置(罗氏)上使用具有45个循环的标准qRT-PCR方案运行。使用ΔΔCt方法{Livak:2001is}计算相对基因表达量,将其标准化到GAPDH、TBP或HPRT。
与来自相同肿瘤活检体的经对照组处理切片相比,在短期的离体司美替尼处理之后,肿瘤切片表达更多与产生抗性相关的基因的患者可能产生针对基于司美替尼的癌症疗法的抗性,所述基因选自包括以下的群组:SOX、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
3.肿瘤切片的免疫组织化学分析
为了防止对组织切片的损坏,使用小条硝酸纤维膜将其提离Millicell插入物。然后将具有组织切片的条带转移到4%多聚甲醛。在24小时之后,将附著硝酸纤维膜的肿瘤切片转移到70%乙醇或直接包埋于石蜡中且根据标准方案分割。使用高压锅,在98℃下在EDTA缓冲液(pH 9)(Dako S2367)中烹煮石蜡区段20分钟。用过氧化酶块(Dako S2023)阻断区段10分钟,与在稀释缓冲液(Dako S2022)中稀释到2μg/ml的抗SOX2抗体(sc365823)一起培育1小时,并且与二级抗体(Envision Mouse,Dako K4001)一起培育30分钟。所有步骤都在室温下进行。使用根据Gill II(Merck 1051752500)改性的苏木紫(haematoxylin)溶液进行核对比染色持续2秒。在脱水之后,使用Tissue-Tek膜盖玻片(Tissue-Tek FilmCoverslipper)(Sakura,4742)为载片盖上盖玻片。
与来自相同肿瘤活检体的经对照组处理切片相比,在短期的离体司美替尼处理之后,肿瘤切片表达更多SOX2的患者可能产生针对基于司美替尼的癌症疗法的抗性。
实例2-与抗性抑制剂组合的适用于治疗癌症的化合物
1.筛选和获取
在第1天,将A375细胞以1400个细胞/孔接种到384孔板中的补充有10%FCS和2mML-谷氨酰胺的DMEM中。将板保持于加湿的细胞培养箱(21%O2,5%CO2)中,且使其恢复16小时。在第2天,分别用最终浓度为1μM和0.5μM的PLX4720和AZD6244处理细胞。同时,用最终浓度为5μM的FDA批准的药物(表1)的库处理细胞。将板保持于加湿的细胞培养箱(21%O2,5%CO2)中,且使其恢复24小时。在第3天,板用PBS洗涤三次并且在室温下用最终浓度2%的PFA固定10分钟。板用PBS洗涤三次,并且在4℃下与最终浓度0.2%的Triton-X(于PBS中)一起培育10分钟。板用PBS洗涤三次,并且在4℃下与最终浓度0.2%的Triton-X(于PBS中)一起培育10分钟。板用PBS洗涤三次,并且在4℃下与最终浓度1%的甘氨酸(于PBS中)一起培育10分钟。板用PBS洗涤三次,并且与最终浓度0.8μg/ml的Sox-2抗体(SantaCruz,E-4,sc-365823)(在0.05%Tween 20/PBS中)一起培育过夜。在第4天,板用PBS洗涤三次。板在室温下与最终浓度2μg/ml的二级抗体(A-11029,山羊抗小鼠alexa-488,2mg/ml)(用CMF-PBS+0.05%Tween 20稀释)一起培育1小时。板用PBS洗涤三次,并且在室温下与最终浓度6.7μg/ml的碘化丙锭和0.2mg/ml的RNA酶A一起培育1小时。在1小时之后,板用acumen cellestia(TTP Labtech)读取。对此,荧光团在488nm下激发且在FL3(核染色)和FL2(二级抗体)中测量信号。在一个月内一式两份地进行筛选。
2.预加工
通过标准标准化程序(Malo,《自然生物技术(Nat Biotech)》,2006)去除板与板之间的整体变化。根据惯例,基于Z'因子评价分析质量。在板制备期间可产生板内逐行或逐列的条纹模式以及边缘效果。这些模式使用Tuckey的中值打磨方法(median polish method)(Tukey,马萨诸塞州雷丁(Reading Massachusetts):Addison-Wesley,1977)或通过使用loess函数减去平稳多项式(smooth polynomial)(Boutros,《基因组生物学(GenomeBiology)》,2006)消除。
3.差异活性分析
按照Prummer等人(Prummer,《生物分子筛选杂志(J Biomol Screen)》,2012)中概述的工作流程分析差异活性。简单来说,对于化合物的每一单剂量测量,针对其活性与阴性对照组不可区分的虚无假设进行Z-测试。为了使此有效,检查阴性对照组的活性的分布是否正常。对于每个板稳健地估计分布的均值和方差,并且适当时,在一系列连续板中平稳地计算平均值。
半自动化工作流程实施于《统计计算的R环境(R environment for statisticalcomputing)》(Huber,《自然方法(Nat Methods)》,2015)中。
表1
Claims (18)
1.一种用于测定癌细胞或肿瘤细胞是否将对化学物质产生抗性的方法,其中所述方法包括以下步骤:
a)将包括或由从诊断患有癌症的个体获得的癌细胞或肿瘤细胞组成的一个或多个样品暴露于化学物质,其中所述诊断患有癌症的个体先前未给予过所述化学物质;
b)测定a)中所使用的所述一个或多个样品中与产生癌症药物抗性相关的基因的表达量;
c)测定来自所述诊断患有癌症的个体的所述一个或多个样品中与b)中相同的所述基因的表达量,所述样品未暴露于a)中所用的所述化学物质;
其中b)中测定的表达量与c)中测定的所述表达量相比升高指示所述样品中所包括的癌细胞或肿瘤细胞对所述化学物质产生抗性。
2.一种用于测定先前诊断患有癌症的个体是否将对用于治疗所述癌症的化学物质产生抗性的方法,其中所述方法包括以下步骤:
a)将包括或由从所述诊断患有癌症的个体获得的肿瘤细胞癌组成的一个或多个样品暴露于化学物质,其中所述诊断患有癌症的个体先前未给予过所述化学物质;
b)测定a)中所使用的所述一个或多个样品中与产生癌症药物抗性相关的基因的表达量;
c)测定来自所述诊断患有癌症的个体的所述一个或多个样品中与b)中相同的所述基因的表达量,所述样品未暴露于a)中所用的所述化学物质;
其中所述诊断患有癌症的个体在获得所述一个或多个样品之前未给予过a)中所用的所述化学物质,并且其中b)中测定的表达量与c)中测定的所述表达量相比升高指示患者对所述化学物质产生抗性。
3.根据权利要求1或2所述的方法,其中所述一个或多个样品通过活检获得。
4.根据权利要求1或2所述的方法,其中所述样品由血液中的循环肿瘤细胞获得。
5.根据前述权利要求中任一项所述的方法,其中与产生抗性相关的所述基因是选自由以下组成的群组的基因:SOX2、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
6.根据权利要求5所述的方法,其中与产生抗性相关的所述基因为SOX2。
7.根据前述权利要求中任一项所述的方法,其中癌症为非黑素瘤皮肤癌、食管胃腺癌、成胶质细胞瘤、膀胱癌、膀胱尿道上皮癌、食管胃癌、黑素瘤、非小细胞肺癌、子宫内膜癌、宫颈腺癌、食管鳞状细胞癌、乳癌、头颈鳞状细胞癌、生殖细胞肿瘤、小细胞肺癌、卵巢癌、软组织肉瘤、肝细胞癌、结肠直肠腺癌、宫颈鳞状细胞癌、胆管癌、前列腺癌、上尿路尿道上皮癌、弥漫性神经胶质瘤、结肠直肠癌、壶腹癌、肾上腺皮质癌、头颈癌、肾透明细胞癌、肝胆癌、神经胶质瘤、非霍奇金淋巴瘤(non-Hodgkin lymphoma)、间皮瘤、唾液腺癌、肾非透明细胞癌、杂类神经上皮肿瘤、嗜铬细胞瘤、胸腺肿瘤、多发性骨髓瘤、肾细胞癌、骨癌、胰腺癌、白血病、周围神经系统肿瘤、甲状腺癌、B成淋巴细胞白血病、单克隆B细胞淋巴细胞增多、淋巴瘤、毛状细胞白血病、急性骨髓白血病、威尔姆斯肿瘤(Wilms tumor),尤其黑素瘤和非小细胞肺癌。
8.根据前述权利要求中任一项所述的方法,其中所述化学物质为受体酪氨酸激酶(RTK)的抑制剂、EGFR路径的抑制剂(EGFRi)或MAPK路径的抑制剂(MAPKi),其中优选地,所述MAPKi为B-Raf的抑制剂(BRAFi)、MEK的抑制剂(MEKi)或ERK的抑制剂(ERKi)。
9.根据权利要求8所述的方法,其中所述
i)所述BRAFi为维罗非尼(vemurafenib)、达拉非尼(dabrafenib)、
康奈非尼(encorafenib)、LGX818、PLX4720、TAK-632、MLN2480、SB590885、XL281、BMS-908662、PLX3603、RO5185426、GSK2118436或RAF265,
ii)所述MEKi为AZD6244、曲美替尼(trametinib)、司美替尼(selumetinib)、考比替尼(cobimetinib)、贝美替尼(binimetinib)、MEK162、RO5126766、GDC-0623、PD 0325901、CI-1040、PD-035901、寄端霉素(hypothemycin)或TAK-733,
ⅲ)所述ERKi为尤仙替尼(ulixertinib)、去氢钩藤碱(corynoxeine)、SCH772984、XMD8-92、FR 180204、GDC-0994、ERK5-IN-1、DEL-22379、BIX 02189、ERK抑制剂(CAS编号1049738-54-6)、ERK抑制剂III(CAS编号331656-92-9)、GDC-0994、和厚朴酚(honokiol)、LY3214996、CC-90003、三角叶薯蓣皂苷(deltonin)、VRT752271、TIC10、黄芪甲苷IV(astragaloside IV)、XMD8-92、VX-11e、葫芦素(mogrol)或VTX11e,和/或
iv)所述EGFRi为西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、扎芦木单抗(zalutumumab)、尼妥珠单抗(nimotuzumab)、马妥珠单抗(matuzumab)、吉非替尼(gefitinib)、埃罗替尼(erlotinib)、拉帕替尼(lapatinib)、来那替尼(neratinib)、凡德他尼(vandetanib)、耐妥珠单抗(necitumumab)、奥希替尼(osimertinib)、阿法替尼(afatinib)、AP26113、EGFR抑制剂(CAS编号879127-07-8)、EGFR/ErbB-2/ErbB-4抑制剂(CAS编号881001-19-0)、EGFR/ErbB-2抑制剂(CAS编号179248-61-4)、EGFR抑制剂II(BIBX1382,CAS编号196612-93-8)、EGFR抑制剂III(CAS编号733009-42-2)、EGFR/ErbB-2/ErbB-4抑制剂II(CAS编号944341-54-2)或PKCβII/EGFR抑制剂(CAS编号145915-60-2)。
10.一种与第二化学物质组合用于治疗患者的癌症的化学物质,所述患者使用根据权利要求1到7中任一项所述的方法测定为产生对所述化学物质的抗性,其中所述第二化学物质抑制与产生癌症药物抗性相关的基因的表达。
11.一种一种或多种化学物质的用途,所述一种或多种化学物质与另一化学物质组合用于治疗使用根据权利要求1到7中任一项所述的方法测定为产生对所述化学物质的抗性的患者,所述另一化学物质抑制与对于一种或多种第一化学物质产生癌症药物抗性相关的一种或多种基因的表达。
12.一种产品,其含有一种或多种化学物质与另一化学物质的组合,所述一种或多种化学物质使用根据权利要求1到7中任一项所述的方法测定为在肿瘤细胞癌中诱发癌症药物抗性,所述另一化学物质抑制与对于所述第一化学物质产生癌症药物抗性相关的一种或多种基因的表达。
13.根据权利要求10所述的供使用的化学物质、根据权利要求11所述的用途和根据权利要求12所述的产品,其中癌症为非黑素瘤皮肤癌、食管胃腺癌、成胶质细胞瘤、膀胱癌、膀胱尿道上皮癌、食管胃癌、黑素瘤、非小细胞肺癌、子宫内膜癌、宫颈腺癌、食管鳞状细胞癌、乳癌、头颈鳞状细胞癌、生殖细胞肿瘤、小细胞肺癌、卵巢癌、软组织肉瘤、肝细胞癌、结肠直肠腺癌、宫颈鳞状细胞癌、胆管癌、前列腺癌、上尿路尿道上皮癌、弥漫性神经胶质瘤、结肠直肠癌、壶腹癌、肾上腺皮质癌、头颈癌、肾透明细胞癌、肝胆癌、神经胶质瘤、非霍奇金淋巴瘤、间皮瘤、唾液腺癌、肾非透明细胞癌、杂类神经上皮肿瘤、嗜铬细胞瘤、胸腺肿瘤、多发性骨髓瘤、肾细胞癌、骨癌、胰腺癌、白血病、周围神经系统肿瘤、甲状腺癌、B成淋巴细胞白血病、单克隆B细胞淋巴细胞增多、淋巴瘤、毛状细胞白血病、急性骨髓白血病、威尔姆斯肿瘤,尤其黑素瘤和非小细胞肺癌。
14.根据权利要求10或权利要求13所述的供使用的化学物质、根据权利要求11或权利要求13所述的用途和根据权利要求12或权利要求权利要求13所述的产品,其中所述化学物质为受体酪氨酸激酶(RTK)的抑制剂、EGFR路径的抑制剂(EGFRi)、MAPK路径的抑制剂(MAPKi)或用于癌症免疫疗法的试剂,其中优选地,所述MAPKi为B-Raf的抑制剂(BRAFi)、MEK的抑制剂(MEKi)或ERK的抑制剂(ERKi)。
15.根据权利要求14所述的供使用的化学物质、用途和产品,其中所述
i)所述BRAFi为维罗非尼、达拉非尼、康奈非尼、LGX818、PLX4720、TAK-632、MLN2480、SB590885、XL281、BMS-908662、PLX3603、RO5185426、GSK2118436或RAF265,
ii)所述MEKi为AZD6244、曲美替尼、司美替尼、考比替尼、贝美替尼、MEK162、RO5126766、GDC-0623、PD 0325901、CI-1040、PD-035901、寄端霉素或TAK-733,
ⅲ)所述ERKi为尤仙替尼、去氢钩藤碱、SCH772984、XMD8-92、FR 180204、GDC-0994、ERK5-IN-1、DEL-22379、BIX 02189、ERK抑制剂(CAS编号1049738-54-6)、ERK抑制剂III(CAS编号331656-92-9)、GDC-0994、和厚朴酚、LY3214996、CC-90003、三角叶薯蓣皂苷、VRT752271、TIC10、黄芪甲苷IV、XMD8-92、VX-11e、葫芦素或VTX11e,
iv)所述EGFRi为西妥昔单抗、帕尼单抗、扎芦木单抗、尼妥珠单抗、马妥珠单抗、吉非替尼、埃罗替尼、拉帕替尼、来那替尼、凡德他尼、耐妥珠单抗、奥希替尼、阿法替尼、AP26113、EGFR抑制剂(CAS编号879127-07-8)、EGFR/ErbB-2/ErbB-4抑制剂(CAS编号881001-19-0)、EGFR/ErbB-2抑制剂(CAS编号179248-61-4)、EGFR抑制剂II(BIBX 1382,CAS编号196612-93-8)、EGFR抑制剂III(CAS编号733009-42-2)、EGFR/ErbB-2/ErbB-4抑制剂II(CAS编号944341-54-2)或PKCβII/EGFR抑制剂(CAS编号145915-60-2);和/或
v)免疫疗法中使用的所述试剂为靶向CD52、PD-L1、CTLA4、CD20或PD-1的试剂,能够与本发明化合物组合使用的试剂包含例如阿伦珠单抗(alemtuzumab)、阿特珠单抗(atezolizumab)、伊匹单抗(ipilimumab)、纳武单抗(nivolumab)、奥法木单抗(ofatumumab)、派立珠单抗(pembrolizumab)、利妥昔单抗(rituximab)。
16.根据权利要求10和13到15中任一项所述的供使用的化学物质、根据权利要求11和13到15中任一项所述的用途和根据权利要求12和13到15中任一项所述的产品,其中抑制与产生癌症药物抗性相关的基因的表达的所述第二化学物质抑制选自由以下组成的群组的基因:SOX2、Nanog、OCT4、FGF4、FBX15、FOXP4、KLF9、CD24、CD271、CD36、ITLN2、TNFSF12、NOX3、CLEC7A、ACYAP1、UNC5C、UNC5D、MUC16、VAV3、FOXD3、VGLL3、ALPP、C3、F2R、ENPP2、ETV4、NTNG1、NTRK2、ROBO1和ROBO2。
17.根据权利要求16所述的供使用的化学物质、用途和产品,其中与产生抗性相关的所述基因为SOX2。
18.根据权利要求10和13到18中任一项所述的供使用的化学物质、根据权利要求11和13到18中任一项所述的用途和根据权利要求12和13到18中任一项所述的产品,其中所述第二化学物质选自由以下组成的群组:西曲溴铵(cetrimonium bromide)、伊达比星盐酸盐(idarubicin·hcl)、来那替尼(neratinib)(hki-272)、异硫氰酸苯甲酯(benzylisothiocyanate)、伏立诺他(vorinostat)、吐根素二盐酸盐(emetine dihydrochloride)、道诺霉素盐酸盐(daunorubicin hydrochloride)、更生霉素(dactinomycin)、奎西诺他(quisinostat)(jnj26481585)、氯硝柳胺(niclosamide)、小红莓(doxorubicin)、pci-24781(阿贝辛他(abexinostat))、毛花甙丙(lanatoside c)、帕比司他(panobinostat)(lbh589)、沙利霉素(salinomycin)钠、溴沙定(broxaldine)、替尼泊甙(teniposide)、浦西诺他(pracinostat)(sb939)、阿扎胞苷(azacitidine)、高三尖杉酯碱(homoharringtonine)、吖啶琐辛(acrisorcin)、氯化特洛尼姆(tolonium chloride)、拉多替尼(radotinib)、阿莫地喹二盐酸盐(amodiaquine dihydrochloride)、苄索氯铵(benzethonium chloride)、西达本胺(chidamide)、cudc-101、司拉克丁(selamectin)、汉防己碱(tetrandrine)、贝林诺他(belinostat)(pxd101)、依曲韦林(etravirine)(tmc125)、安西奈德(amcinonide)、奥苯达唑(oxibendazole)、乙酰基-l-亮氨酸(acetyl-l-leucine)、氯喔星(chloroxine)、纳布卡辛(napabucasin)、雷米诺他(resminostat)、碘苷(idoxuridine)、硫鸟嘌呤(tioguanine)、环己酰亚胺(cycloheximide)、曲氟尿苷(trifluridine)、17,21二丙酸倍他米松(betamethasone 17,21,dipropionate)、多韦替尼(dovitinib)(tki-258)二乳酸、秋水仙碱(colchicine)、莫塞诺他(mocetinostat)(mgcd0103)、舒尼替尼(sunitinib)、培利替尼(pelitinib)(ekb-569)、哌马色林(pimavanserin)、乙氧黄酮(efloxate)、tg101348(sar302503)、丙酸氯倍他索(clobetasolpropionate)、甲基泼尼松龙丁二酸钠(methylprednisolone sodium succinate)、乙酸二氯松(dichlorisone acetate)、阿苯达唑(albendazole)、恩替诺特(entinostat)(ms-275)、氟尼缩松(flunisolide)、青蒿醇(artenimol)、氨吖啶(aminacrine)、氟米松(flumethasone)、罗利诺他(rocilinostat)(acy-1215)、溴硝丙二醇(bronopol)、短杆菌肽(gramicidin)(所示为短杆菌肽a)、阿巴汀(abamectin)(所示为阿佛菌素b1a(avermectinb1a))、双硫仑(disulfiram)、二氟泼尼酯(difluprednate)、乙酰碘佐酸(acetriazoicacid)、乙酸异氟泼尼龙(isoflupredone acetate)、ly2835219、顺丁烯二酸哌克昔林(perhexiline maleate)、甲麦角林(metergoline)、福美司坦(formestane)、莫能菌素钠(monensin sodium)、氟尿苷(floxuridine)、泼尼卡酯(prednicarbate)、地塞米松磷酸钠(dexamethasone sodium phosphate)、来氟米特(leflunomide)、丙酸卤贝他索(halobetasol propionate)、西罗莫司(sirolimus)、依昔黄酮(ipriflavone)、尼达尼布(nintedanib)(bibf 1120)、扑蛲灵(pyrvinium)、双羟萘酸盐(pamoate)、芦氟沙星盐酸盐(rufloxacin hydrochloride)、福他布林(fosbretabulin)(磷酸考布他汀a4(combretastatin a4 phosphate,ca4p))二钠、二乙酸曲安西龙(triamcinolonediacetate)、奥太那班(otenabant)(cp-945598)盐酸盐、抑肽酶(aprotinin)、丙酸氟替卡松(fluticasone propionate)、阿姆瓦替尼(amuvatinib)(mp-470)、甲基苄索氯铵(methylbenzethonium chloride)、芬苯达唑(fenbendazole)、布比卡因盐酸盐(bupivacaine hydrochloride)、倍他米松(betamethasone)、特戊酸氟米松(flumethazonepivalate)、硫鸟嘌呤(thioguanine)、顺丁烯二酸替加色罗(tegaserod maleate)、泼尼松龙乙酸盐(prednisolone acetate)、二氢卟吩二酮(chlorindione)、半丁二酸氢皮质酮(hydrocortisone hemisuccinate)、乙酸地塞米松(dexamethasone acetate)、乙酸氟氢可的松(fludrocortisone acetate)、伊佛霉素(ivermectin)、半硫酸普鲁黄(proflavinehemisulfate)、兰索拉唑(lansoprazole)、赛度替尼(cerdulatinib)(prt062070,prt2070)、萨利方金(salifungin)、哈西奈德(halcinonide)、福多司坦(fudosteine)、特非那定(terfenadine)、醋酸氟轻松(fluocinonide)、海克替啶(hexetidine)、青蒿琥酯(artesunate)、氟轻松(fluocinolone acetonide)、利福平(rifampin)、曲安西龙(triamcinolone)、唑吡坦(zolpidem)、二乙丙苯嗪(ethopropazine)盐酸盐、瑞格非尼(regorafenib)(bay 73-4506)、特拉唑嗪盐酸盐(terazosin hydrochloride)、丹参酮iia-磺酸钠(tanshinone iia-sulfonic sodium)、诺考达唑(nocodazole)、三氯生(triclosan)、氯羟吡啶(clopidol)、甲苯磺酸索拉非尼(sorafenib tosylate)、磺胺二甲异嘧啶(sulfisomidine)、亚甲基蓝(methylene blue)、克卓替尼(crizotinib)(pf-02341066)、海葱次甙a(proscillaridin a)、右布洛芬(dexibuprofen)、三氟丙嗪盐酸盐(triflupromazine hydrochloride)、吡贝地尔盐酸盐(piribedil hydrochloride)、卡莫氟(carmofur)、獐牙菜苦苷(swertiamarin)、甲苯磺酸舒它西林(sultamicillintosylate)、人参皂苷rc(ginsenoside rc)、依托贝特(etofibrate)、氯化十六烷基吡锭(cetylpyridinium chloride)、雷贝拉唑钠(rabeprazole sodium)、阿立必利盐酸盐(alizapride hydrochloride)、氨基乙酰丙酸甲酯·盐酸盐(methyl aminolevulinate·hcl)、托匹司他(topiroxostat)、四水合氯屈膦酸二钠(disodium clodronatetetrahydrate)、阿莫沙平(amoxapine)、贝达喹啉(bedaquiline)(tmc207;r207910)、奥替尼啶(octenidine)、依卡倍特钠(ecabet sodium)、芹黄素(apigenin)、格隆溴铵碘(glycopyrrolate iodide)、蒙脱石钠(sodium montmorillonite)、氢皮质酮(hydrocortisone)、巴巴丁(barbadin)、CCS1477、SGC-CBP30、CPI-637、PF-CBP1、ICG,001,PRI-724、A-485、C646、4-甲硫基-2-氧代丁酸(MTOB)、HIPP衍生物、环肽CP61、NSC95397、2-(羟亚氨基)-3-苯基丙酸和其4-氯和3-氯类似物、MLN4924、AS1842856、JIB-04、EP-5676、N-草酰甘氨酸(NOG)、吡啶-2,4-二甲酸酯(2,4-PDCA)、普拉地内酯B(pladineolide B)、IDC16、CBL0137、迪福平(difopein)、R18。
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CN112176064A (zh) * | 2020-10-16 | 2021-01-05 | 中国医科大学 | Atxn7l3在肝癌诊断、治疗及预后中的应用 |
WO2022033459A1 (zh) * | 2020-08-10 | 2022-02-17 | 萧乃文 | 双非癌药物用于制备治疗癌症的医药组合物的用途 |
CN114848651A (zh) * | 2022-04-27 | 2022-08-05 | 江苏省人民医院(南京医科大学第一附属医院) | 抑制gusb活性物质在制备提高抗癌疗效药物中的应用 |
CN114989158A (zh) * | 2021-03-02 | 2022-09-02 | 复旦大学 | 组蛋白乙酰转移酶p300溴结构域抑制剂及其药用组合物及其应用 |
CN115677772A (zh) * | 2021-07-30 | 2023-02-03 | 浙江大学智能创新药物研究院 | 一种用于egfr激酶抑制剂的化合物、组合物及其应用 |
WO2023029141A1 (zh) * | 2021-08-30 | 2023-03-09 | 暨南大学 | 奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用 |
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KR20230108030A (ko) | 2022-01-10 | 2023-07-18 | 부산대학교 산학협력단 | Agr2의 동종이량체를 표적으로 하는 에트라비린을 유효성분으로 함유하는 암 예방 또는 치료용 조성물 |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022033459A1 (zh) * | 2020-08-10 | 2022-02-17 | 萧乃文 | 双非癌药物用于制备治疗癌症的医药组合物的用途 |
CN112176064A (zh) * | 2020-10-16 | 2021-01-05 | 中国医科大学 | Atxn7l3在肝癌诊断、治疗及预后中的应用 |
CN114989158A (zh) * | 2021-03-02 | 2022-09-02 | 复旦大学 | 组蛋白乙酰转移酶p300溴结构域抑制剂及其药用组合物及其应用 |
CN115677772A (zh) * | 2021-07-30 | 2023-02-03 | 浙江大学智能创新药物研究院 | 一种用于egfr激酶抑制剂的化合物、组合物及其应用 |
CN115677772B (zh) * | 2021-07-30 | 2023-08-18 | 浙江大学智能创新药物研究院 | 一种用于egfr激酶抑制剂的化合物、组合物及其应用 |
WO2023029141A1 (zh) * | 2021-08-30 | 2023-03-09 | 暨南大学 | 奥替尼啶双盐酸盐在制备抗肿瘤药物中的应用 |
CN114848651A (zh) * | 2022-04-27 | 2022-08-05 | 江苏省人民医院(南京医科大学第一附属医院) | 抑制gusb活性物质在制备提高抗癌疗效药物中的应用 |
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JP7379355B2 (ja) | 2023-11-14 |
EP3714069A1 (en) | 2020-09-30 |
CA3080633A1 (en) | 2019-05-23 |
US20200325543A1 (en) | 2020-10-15 |
KR20200086305A (ko) | 2020-07-16 |
WO2019097078A1 (en) | 2019-05-23 |
AU2018368639A1 (en) | 2020-06-04 |
JP2021503308A (ja) | 2021-02-12 |
AU2018368639A8 (en) | 2020-07-16 |
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