CN1898568A - 增生性疾病对mTOR抑制剂敏感性的生物标志 - Google Patents

增生性疾病对mTOR抑制剂敏感性的生物标志 Download PDF

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CN1898568A
CN1898568A CNA2004800381826A CN200480038182A CN1898568A CN 1898568 A CN1898568 A CN 1898568A CN A2004800381826 A CNA2004800381826 A CN A2004800381826A CN 200480038182 A CN200480038182 A CN 200480038182A CN 1898568 A CN1898568 A CN 1898568A
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A·布莱
H·莱恩
S-M·马伊拉
T·奥赖利
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Abstract

公开了用于确定受试者中增生性疾病对用mTOR抑制剂治疗的敏感性的方法，所述方法包括确定来自该受试者的样品中S6的表达水平和/或磷酸化状态，还公开了相关治疗方法和用途。

Description

增生性疾病对mTOR抑制剂敏感性的生物标志
本发明涉及用于确定增生性疾病诸如癌症对治疗剂，特别是mTOR抑制剂的敏感性的生物标志。
许多mTOR抑制剂具有强效抗增生性质，使它们用于癌症的化学治疗，特别是实体瘤，尤其是晚期实体瘤的化学治疗。然而，还需要mTOR抑制剂的更定向的用途，所述更定向的用途需要鉴定可能对此类活性剂治疗有反应的患者。因此需要用于例如临床试验的生物标志，所述生物标志能预测患者中增生性疾病，例如肿瘤对用mTOR抑制剂治疗的反应。
令人惊奇地发现S640S核糖体蛋白质(另外称为S6)是预测增生性疾病对用mTOR抑制剂治疗的敏感性的有用的生物标志。特别地，发现S6的磷酸化状态与对mTOR抑制剂的敏感性有很好的相关性。当用于处理显示较高水平表达磷酸化S6的癌细胞系时，mTOR抑制剂更可能显示显著的抗增殖作用。S6是40S核糖体亚单位的组分，所述40S核糖体亚单位是mTOR蛋白激酶下游效应子p70 S6激酶的底物。S6的多重磷酸化牵涉到编码蛋白质合成器组分的mRNA的翻译上调，并因此认为在哺乳动物细胞的生长中起主要作用(Volarevic和Thomas，Prog.Nucleic Acid Res.Mol.Biol.2001，65：101-27)。人S6的序列可以以Genbank检索号M20020获得。
一方面，本发明提供了S640S核糖体蛋白质(S6)，特别是磷酸化S6作为生物标志用于确定增生性疾病对用mTOR抑制剂治疗的敏感性的用途。
另一方面，本发明提供了用于确定患者中增生性疾病对用mTOR抑制剂治疗的敏感性的方法，其包括确定来自受试者的样品中S6的表达水平和/或磷酸化状态。
另一方面，本发明提供了选择患有增生性疾病的受试者用于用mTOR抑制剂治疗的方法，其包括通过如以上描述的方法确定每名受试者中增生性疾病对mTOR抑制剂治疗的敏感性，和选择显示磷酸化S6表达增加的受试者用于用mTOR抑制剂治疗的方法。
如文中使用的术语“mTOR抑制剂”包括但不限于雷帕霉素(西罗莫司)或其衍生物。雷帕霉素是已知的由吸水链霉菌(Streptomyces hygroscopicus)产生的大环内酯类抗生素。雷帕霉素的合适的衍生物包括例如式A的化合物
Figure A20048003818200051
其中R1aa是CH3或C3-6炔基，
R2aa是H或-CH2-CH2-OH、3-羟基-2-(羟甲基)-2-甲基-丙酰基或四唑基，和
Xaa是＝O、(H，H)或(H，OH)
条件是当Xaa是＝O并且R1aa是CH3时，R2aa不是H，
或当R2aa是-CH2-CH2-OH是，还包括所述化合物的前体药物，例如其生理学可水解的醚，例如其中R2aa是-CH2-CH2-O-Alk的化合物，Alk是任选在链中由1个或2个氧原子中断的C1-9烷基。
例如在WO 94/09010、WO 95/16691、WO 96/41807、USP 5,362,718或WO 99/15530中公开了式A的化合物，此处将它们引用作为参考。如这些参考文献中公开地或通过这些参考文献中描述的方法的类似方法可以制备它们。
优选的雷帕霉素衍生物是32-脱氧雷帕霉素、16-戊-2-炔氧基-32-脱氧雷帕霉素、16-戊-2-炔氧基-32(S)-二氢-雷帕霉素、16-戊-2-炔氧基-32(S)-二氢-40-O-(2-羟基乙基)-雷帕霉素和更优选地，40-O-(2-羟基乙基)雷帕霉素。雷帕霉素衍生物的其他实例包括例如在USP 5,362,718中公开的CCI779或40-[3-羟基-2-(羟基甲基)-2-甲基丙酸酯]-雷帕霉素或其可药用盐，例如在WO 99/15530中公开的ABT578或40-(四唑基)-雷帕霉素，特别是40-表-(四唑基)-雷帕霉素。雷帕霉素衍生物也可以包括例如在WO98/02441、WO 01/14387和WO 03/64383中公开的所称的雷帕类似物(rapalog)，例如AP23573、AP23464、AP23675或AP23841。雷帕霉素衍生物的其它实例为以TAFA-93、biolimus-7或biolimus-9名称公开的雷帕霉素衍生物。
在给出专利申请或科学出版物的引用的每种情况下，涉及化合物的主题在本申请中引用作为参考。同样包含其可药用盐、对应的外消旋物、非对映异构体、对映体、互变异构体以及文中公开的化合物的对应的结晶修饰(如存在)，例如溶剂化物、水合物和多晶型物。如分别在引用的文献中描述地，可以制备和施用在本发明的组合中用作活性成分的化合物。
增生性疾病可以是良性或恶性增生性疾病，例如良性前列腺增生或瘤性疾病，优选恶性增生性疾病，例如癌症，例如实体瘤，特别是在WO02/66019中公开的晚期实体瘤。“实体瘤”表示肿瘤和/或转移瘤(无论位于何处)而不是淋巴癌，例如脑和其它中枢神经系统肿瘤(例如脑膜、脑、脊髓、脑神经和中枢神经系统的其它部分的肿瘤，例如成胶质细胞瘤或髓质胚细胞瘤)；头和/或颈癌；乳腺肿瘤；循环系统肿瘤(例如心脏、纵隔和胸膜，和其它胸内器官肿瘤、血管瘤和肿瘤相关的血管组织)；排泄系统肿瘤(例如肾、肾盂、输尿管、膀胱、其它和未指定的泌尿器官的肿瘤)；胃肠道肿瘤(例如食道、胃、小肠、结肠、结肠直肠、直肠乙状结肠连接部、直肠、肛门和肛管的肿瘤)、涉及肝脏和肝内胆管、胆囊、胆管的其它和未指定部分、胰腺、其它和消化器官的肿瘤)；头和颈；口腔肿瘤(唇、舌、牙龈、口底、腭和口的其它部分、腮腺、和唾液腺的其它部分、扁桃体、口咽、鼻咽、梨状隐窝、下咽、和唇、口腔和咽的其它部位的肿瘤)；生殖系统肿瘤(例如阴户、阴道、子宫颈、子宫体、子宫、卵巢和与女性生殖器官相关的其它部位、胎盘、阴茎、前列腺、睾丸和与男性生殖器官相关的其它部位的肿瘤)；呼吸道肿瘤(例如鼻腔、中耳、副鼻窦、喉、气管、支气管和肺的肿瘤，例如小细胞肺癌或非小细胞肺癌)；骨骼系统肿瘤(例如四肢的骨和关节软骨、骨关节软骨和其它部位的肿瘤)；皮肤肿瘤(例如皮肤的恶性黑素瘤、非黑素瘤皮肤癌、皮肤基底细胞癌、皮肤鳞状细胞癌、间皮瘤、卡波西肉瘤)；和涉及其它组织的肿瘤，包括外周神经和自主神经系统、结缔组织和软组织、腹膜后腔和腹膜、眼和副器、甲状腺、肾上腺和其它内分泌腺和相关结构的肿瘤、淋巴结的次级和未指定恶性赘生物、呼吸和消化系统的次级恶性赘生物和其它部位的次级恶性赘生物。当上文及随后谈及肿瘤、肿瘤疾病、癌或癌症时，无论肿瘤和/或转移瘤的位置，备选地或此外也包括最初器官或组织和/或任意其它部位的转移瘤。
根据本发明的方法，可以筛选患有此种增生性疾病的受试者以预测他们对mTOR抑制剂的敏感性。可以在体外，例如在来自受试者的生物学组织的样品上进行该方法。样品可以是分离自哺乳动物身体的任意生物学材料，诸如组织、细胞系、血浆或血清、细胞或组织裂解物，优选肿瘤组织。受试者优选为人受试者。
通过基于例如RNA表达或例如蛋白质表达的任意技术手段测定了生物学样品中S6的表达水平和/或磷酸化状态，所述基于RNA表达的技术手段使用例如RT-PCR技术，所述基于蛋白质表达的技术手段使用例如蛋白质印迹、免疫组织化学或ELISA的技术，包括免疫测定、免疫沉淀和免疫电泳测定。优选地，该方法包括测定样品中(例如人)S6蛋白质及特别地，磷酸化S6的表达水平。该方法可以涉及检测S6上任意磷酸化位点的磷酸化。例如，可以测定(例如人)S6在丝氨酸235/236的磷酸化，更优选地测定S6在丝氨酸240/244的磷酸化。
例如，在标准免疫测定形式中用对(例如磷酸化)S6特异的抗体测定(例如磷酸化)S6的水平。也利用ELISA(酶联免疫吸附测定)类型测定、免疫沉淀类型测定、常规蛋白质印迹测定和免疫组织化学测定，使用例如单克隆或多克隆抗体作为生物标志蛋白质的磷酸化S6的水平。
根据已知的免疫方法制备对S6特异的，例如对S6蛋白质或对磷酸化S6特异的多克隆和单克隆抗体。
通过二维(2-D)凝胶电泳也可以测定磷酸化S6水平。2-D凝胶电泳是本领域已知的并且一般涉及沿着第一个方向的等电聚焦(IEF)接着在第二个方向的SDS-PAGE(十二烷基硫酸钠-聚丙烯酰胺凝胶电泳)。例如用抗体通过免疫印迹分析对所得电泳图进行分析。如以上讨论地可以产生或从商业来源(例如Cell Signaling Technology目录#2212；#2215；#2211)获得针对S6蛋白质或磷酸化S6的合适的抗体。
因此本发明提供了筛选患有增生性疾病的受试者以预测他们对用mTOR抑制剂治疗的反应的方法，其包含通过如以上定义的方法确定S6的表达水平和/或磷酸化状态。
另一方面，本发明提供了治疗需要治疗的受试者中增生性疾病的方法，其包含通过如以上描述的方法确定来自受试者的样品中S6的表达水平和/或磷酸化状态，和如果(例如磷酸化的)S6的表达水平升高，用mTOR抑制剂治疗受试者。
来自受试者的特定组织，例如肿瘤组织的样品中发现的水平可以与对照样品比较，所述对照样品为例如来自没有患所述疾病的受试者的正常组织的样品，或来自相同受试者的正常(即非肿瘤)组织的样品。磷酸化S6的升高的水平(例如高于对照水平)预示mTOR抑制剂的有益的治疗作用(即抗增生作用)。例如在某些实施方案中可以由技术人员确定指示使用mTOR抑制剂时升高的水平，在所述实施方案中指示使用mTOR抑制剂治疗，其中样品中磷酸化S6的水平可检测地高于对照水平或所述水平高于对照至少50％、100％、500％或1000％。
此外，可以用该方法选择mTOR抑制剂的合适剂量以对每名患者个别优化治疗。例如当来自受试者的样品显示较高的磷酸化S6水平时，可以选择较低剂量的mTOR抑制剂，并且反之亦然。在此上下文中用于考虑的因素包括正治疗的特定疾病、正治疗的特定哺乳动物、个别患者的临床状态、活性化合物递送的部位、活性化合物的特定类型、施用方法、施用方案、疾病严重度和医学从业者已知的其它因素。待施用的活性化合物的治疗有效量受到此类考虑的支配并且是防止、改善或治疗疾病必需的最低量。此量优选低于对宿主有毒性的量或使宿主对感染显著更易感的量。mTOR抑制剂的适当剂量为例如在WO 02/66019中公开地，例如日剂量率为口服(p.o.)大约0.1至70mg，例如大约0.1至25mg，例如大约0.05至10mg活性成分，作为单次剂量或分份剂量或间歇施用，例如一周一次。通过任意常规途径，特别是经肠，例如经口，例如以片剂、胶囊、饮用溶液的形式或肠胃外，例如以可注射溶液或悬浮液的形式施用雷帕霉素或其衍生物，例如式A的化合物，所述形式含有例如约0.1％至约99.9％，优选约1％至约60％活性成分。
实施例1
将人肿瘤细胞，例如40-O-(2-羟基乙基)雷帕霉素-敏感的MCF7、BT549或LNCap细胞系(IC50在nM以下范围)对作为比较的40-O-(2-羟基乙基)雷帕霉素抗性PC3M细胞系(IC50在＞100nM的范围)，以及中等雷帕霉素敏感的细胞系(IC50在1nM-100nM范围)，诸如DU145、HCC1937和MDA-MB231加到96孔板(在100μl培养基中含500至5000个细胞/孔)并孵育24小时。随后，在单独的孔中制备mTOR抑制剂，例如式A的化合物，例如40-O-(2-羟基乙基)雷帕霉素的稀释系列并将稀释液加入到孔中。然后将细胞再孵育4天。第5天进行亚甲蓝染色并确定结合的染料的量(与结合染料的存活细胞的数目成比例)。随后用Softmax1.2.0软件确定IC50。
如以上培养至50-70％汇合的相同的肿瘤细胞系用常规培养基(10％v/v FCS)再培养。24小时后，制备蛋白质裂解物并将20μg裂解物用电泳分离并通过半干电印迹转移到聚偏二氟乙烯(PVDF)上。用抗磷-S6或抗S6蛋白质抗体探测印迹并用增强的化学发光显示修饰的蛋白质。每种细胞系中S6磷酸化的相对强度显示并列举为：0(没有观察到磷酸化)、0.5、1、2、3或4(观察到最大磷酸化)。
相同细胞系中磷酸化S6水平与mTOR抑制剂的IC50测定结果的比较表明mTOR抑制剂的抗增殖活性增加与磷酸化S6水平增加有显著相关性(例如在丝氨酸240和244上S6的磷酸化[使用Cell SignalingTechnologyR抗体目录号2215]：通过Spearman Rank相关性分析n＝7，R＝-0.746，p＝0.00384)。当用磷酸化MAPK/ERK1/2进行相同分析时，没有观察到相似相关性(例如在苏氨酸202和酪氨酸204上ERK1/2磷酸化[使用Cell Signaling TechnologyR抗体目录号9106]；n＝7，R＝-0.123，p＝0.781)。
为了预测例如受试者中肿瘤对mTOR抑制剂的敏感性，用含有来自受试者肿瘤组织的样品代谢人肿瘤细胞系进行了如以上描述的相似分析。从肿瘤组织样品获得的磷酸化S6水平可以与从对照组织获得的磷酸化S6水平或从人肿瘤细胞系获得的数据进行比较以预测对mTOR抑制剂的可能反应。

Claims (13)

1.S6作为生物标志的用途，用于确定受试者中增生性疾病对用mTOR抑制剂治疗的敏感性。
2.S6作为生物标志的用途，用于选择患有增生性疾病的受试者进行mTOR抑制剂治疗。
3.权利要求1或2的用途，其包括使用S6的表达水平和/或磷酸化状态。
4.根据前面权利要求任一项的用途，其包括使用磷酸化S6蛋白质的表达水平。
5.用于确定受试者中增生性疾病对用mTOR抑制剂治疗的敏感性的方法，其包括确定来自所述受试者的样品中S6的表达水平和/或磷酸化状态。
6.根据前面权利要求任一项的方法或用途，其中增生性疾病包含癌症。
7.根据前面权利要求任一项的方法或用途，其中mTOR抑制剂包含雷帕霉素或雷帕霉素衍生物。
8.根据权利要求7的方法或用途，其中雷帕霉素衍生物包含40-O-(2-羟基乙基)雷帕霉素。
9.根据权利要求4至8中任意一项的方法，其包括确定磷酸化S6蛋白质的表达水平。
10.根据权利要求4至9中任意一项的方法，其中样品来自受试者中的肿瘤。
11.根据权利要求4至10中任意一项的方法，其中相对于对照，磷酸化S6的增加的表达预示增生性疾病对用mTOR抑制剂治疗的敏感性。
12.选择患有增生性疾病的受试者进行mTOR抑制剂治疗的方法，其包括通过权利要求4至11任一项描述的方法确定每名受试者中增生性疾病对用mTOR抑制剂治疗的敏感性，并选择显示出磷酸化S6表达升高的受试者进行mTOR抑制剂治疗。
13.治疗需要其的受试者中增生性疾病的方法，其包括通过权利要求4至11任一项中描述的方法确定来自所述受试者的样品中磷酸化S6的表达水平，并且如果磷酸化S6的表达水平升高，那么用mTOR抑制剂治疗所述受试者。
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