CN113056267A - Plk1靶磷酸化状态以及用plk1抑制剂治疗癌症 - Google Patents
Plk1靶磷酸化状态以及用plk1抑制剂治疗癌症 Download PDFInfo
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- CN113056267A CN113056267A CN201980069212.6A CN201980069212A CN113056267A CN 113056267 A CN113056267 A CN 113056267A CN 201980069212 A CN201980069212 A CN 201980069212A CN 113056267 A CN113056267 A CN 113056267A
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Abstract
提供了一种方法,所述方法包括通过在以下时间测量PLK1靶的磷酸化来确定患者癌症中的PLK1活性:(a)在用polo样激酶1(PLK1)抑制剂处理(i)患者或(ii)来自该患者的癌症样品之前,以及(b)处理之后。还提供了一种方法,所述方法包括通过测量没有用polo样激酶1(PLK1)抑制剂处理的情况下PLK1靶的磷酸化来确定患者癌症中的PLK1活性。
Description
相关申请的交叉引用
本申请要求2018年8月26日提交并且通过引用整体并入本文的美国临时申请第62/722,934号的权益。
发明背景
(1)发明领域
本申请总体上涉及癌症治疗。更具体地,本申请提供了用于通过确定polo样激酶1(PLK1)抑制剂抑制患有癌症的患者中PLK1靶磷酸化的能力来评估癌症对PLK1抑制剂的响应性的方法。
(2)相关领域的描述
Polo样激酶1
Polo样激酶1(PLK1)是丝氨酸/苏氨酸蛋白激酶家族5个成员中被最充分表征的成员,并且强烈促进通过有丝分裂的细胞进程。PLK1在细胞周期的有丝分裂(M)期发挥若干重要功能,包括调节中心体成熟和纺锤体组装,从染色体臂上去除黏连蛋白,灭活后期促进复合物/细胞周期体(APC/C)抑制剂,以及调节有丝分裂退出和胞质分裂(Stebhardt,2010)。PLK1在中心体功能和双极纺锤体的组装中起着关键作用。PLK1还充当p53家族成员的负调节物,导致p53/TP53的泛素化和随后的降解,抑制p73/TP73介导的促凋亡功能和极光激酶A的辅因子bora的磷酸化/降解。在有丝分裂的不同时期期间,PLK1定位于中心体、动粒(kinetochores)和中央纺锤体。PLK1在各种人类癌症中异常过表达,所述人类癌症包括急性髓系白血病(AML)、乳腺癌、卵巢癌、非小细胞肺癌、结肠癌、头颈癌、子宫内膜癌和食管癌,并且PLK1与细胞增殖和不良预后相关(Degenhardt,2010;Liu等人,2017;CancerGenome Atlas)。
Onvansertib
ONVANSERTIB
Onvansertib(在美国专利8,927,530中还被称为PCM-075,NMS-1286937,NMS-937,“式(I)的化合物”;IUPAC名称1-(2-羟乙基)-8-{[5-(4-甲基哌嗪-1-基)-2-(三氟甲氧基)苯基]氨基}-4,5-二氢-1H-吡唑[4,3-h]喹唑啉-3-甲酰胺)是第一种通过口服途径施用进入临床试验的PLK1特异性ATP竞争性抑制剂,在不同的临床前模型中被证明具有抗肿瘤活性(Beria等人,2011;Hartsink-Segers等人,2013;Sero等人,2014;Valsasina等人,2012;Casolaro等人,2013)。该化合物在增殖测定中显示出高效力,对大量细胞系(包括实体瘤以及血液肿瘤二者)具有低纳摩尔活性。在小鼠中,Onvansertib在口服施用之后以良好耐受剂量有效引起癌细胞系中有丝分裂细胞周期停滞,随后凋亡,并且抑制异种移植肿瘤的生长,具有明确的PLK1相关作用机制。此外,onvansertib显示出在与批准的细胞毒性药物(诸如伊立替康)的组合疗法中的活性,其中在HT29人类结肠腺癌异种移植物中,与单独的每种剂相比肿瘤消退增强(Valsasina等人,2012;还参见美国专利8,927,530),并且显示了在与阿糖胞苷的组合疗法中在播散性AML模型中动物的延长存活期(Valsasina等人,2012;Casolaro等人,2013)。Onvansertib在啮齿动物和非啮齿动物物种中具有有利的药理学参数和良好的口服生物可利用度,以及在使用各种给药方案的不同非临床模型中证明的抗肿瘤活性,这可能在给药方案中潜在提供高度的灵活性,值得在临床环境中进行研究。Onvansertib与先前的PLK抑制剂相比有若干优点,包括仅对PLK1的高选择性、口服可用性和~24小时的半衰期。
在美国的一个单独研究中心,已经在患有晚期/转移性实体瘤的成年受试者中进行了onvansertib的1期剂量递增研究。该研究的主要目的是确定患有晚期/转移性实体瘤的成人受试者中onvansertib的最大耐受剂量(MTD)。该研究的次要目的是定义抗肿瘤活性。在该研究中,确定了推荐的2期24mg/m2剂量,并且16名可评估患者中的5名具有稳定的病情。
基于以上所述,对于富集对onvansertib或其他PLK1抑制剂具有更大响应可能性的受试者子集的方法存在需求。本发明通过提供通过确定PLK1抑制剂对PLK1靶磷酸化的抑制程度来预测PLK1抑制剂对癌症的功效的方法满足了该需求。
发明概述
提供了一种方法,所述方法包括通过在以下时间测量PLK1靶的磷酸化来确定患者癌症中的PLK1活性:(a)在用polo样激酶1(PLK1)抑制剂处理(i)患者或(ii)来自该患者的癌症样品之前,以及(b)处理之后。
附图的几个视图的简要描述
图1A是显示用onvansertib(PCM-075)和阿糖胞苷或地西他滨处理的三名患者的血液中的白血病细胞的图。
图1B是显示用onvansertib处理的三名患者的骨髓中的白血病细胞的图。
图2A是TCTP的PLK1磷酸化被onvansertib(PCM-075)抑制的图示。
图2B示出了TCTP的PLK1磷酸化被onvansertib(PCM-075)抑制的蛋白印迹。
图2C示出了onvansertib(PCM-075)抑制AML细胞系中TCTP的PLK1磷酸化的蛋白印迹试验。
图3A是显示用onvansertib(PCM-075)和LDAC(阿糖胞苷)处理的三名患者的血液中的白血病细胞的图。
图3B示出了图3A中鉴定的患者onvansertib(PCM-075)在处理之前以及之后的TCTP的PLK1磷酸化的蛋白印迹。
图4A是显示用onvansertib(PCM-075)和地西他滨处理的三名患者的血液中的白血病细胞的图。
图4B示出了图4A中鉴定的患者在onvansertib(PCM-075)处理之前以及之后的TCTP的PLK1磷酸化的蛋白印迹。
图5示出了对图3和图4中鉴定的患者在onvansertib(PCM-075)处理之前以及之后的TCTP的PLK1磷酸化进行定量的蛋白印迹和图。
图6示出了用一剂(D1)或四剂(D5)onvansertib(PCM-075)处理患者之前以及之后的TCTP的PLK1磷酸化的蛋白印迹。
图7是用onvansertib处理的响应者和无响应者在处理之前以及之后的%pTCTP的数据图。
图8示出了在用一剂onvansertib处理患者之前以及之后的TCTP的PLK1磷酸化的蛋白印迹,以及显示处理之后相对于处理之前的%pTCTP变化的图。
图9A是显示其TCTP磷酸化被onvansertib抑制的患者(生物标志物阳性)以及其TCTP磷酸化未被onvansertib抑制的患者(生物标志物阴性)中的%骨髓母细胞(blast)变化的图。
图9B是生物标志物阳性患者和生物标志物阴性患者相对于基线的%骨髓母细胞变化的瀑布图。
图10是用于确定TCTP磷酸化的免疫PCR的实例的图示。
发明详述
除非上下文另有清楚地指示,否则如本文使用的,单数形式“一(a)”、“一(an)”和“该(the)”意图也包括复数形式。此外,除非上下文清楚地另有说明,否则“或”的使用意图包括“和/或”。
本发明部分基于这样的发现,即PLK1抑制剂在治疗患者癌症中的有效性可以通过确定PLK1抑制剂是否能够抑制癌细胞中的PLK1活性来快速且容易地确定。该发现由下文实施例中描述的研究确定。这些实施例确定了,通过PLK1抑制剂(onvansertib)对患者癌症(急性髓系白血病)的PLK1靶(TCTP)的磷酸化的抑制鉴定对用PLK1抑制剂处理患者有响应的癌症。有了这些结果,本领域技术人员将会理解,测量任何PLK1抑制剂对任何患者的任何癌症中的任何PLK1靶的磷酸化的抑制将鉴定对用该PLK1抑制剂处理有响应的癌症。
因此,在一些实施方案中,本发明涉及一种方法,该方法包括
通过在以下时间测量PLK1靶的磷酸化来确定患者癌症中的PLK1活性:(a)在用polo样激酶1(PLK1)抑制剂处理(i)患者或(ii)来自该患者的癌症样品之前,以及(b)处理之后。
在这些方法中,可以测量任何PLK1靶的磷酸化。可以评估磷酸化降低的PLK1磷酸化靶的非限制性实例包括TRF1、Mre11、PTP1B、Orc2、Hbo1、BubR1、WDR62、IRS2、LSD1、胱天蛋白酶-8、NudC、PTEN、BORA、BUB1B/BUBR1、CCNB1、CDC25C、CEP55、ECT2、ERCC6L、FBXO5/EMI1、FOXM1、KIF20A/MKLP2、CENPU、NEDD1、NINL、NPM1、NUDC、PKMYT1/MYT1、KIZ、PPP1R12A/MYPT1、PRC1、RACGAP1/CYK4、SGO1、STAG2/SA2、TEX14、TOPORS、p73/TP73、WEE1、HNRNPU和翻译控制肿瘤蛋白(translational control tumor protein,TCTP)。在一些实施方案中,评估磷酸化抑制的PLK1靶是TCTP(UniProtKB P13693)。PLK1在丝氨酸46和苏氨酸65处磷酸化TCTP(Cucchi等人,2010;Acunzo等人,2014)。
在一些实施方案中,用PLK1抑制剂处理患者,并且在处理之前以及之后采集癌症样品,并且测量这些样品中的靶的磷酸化,以确定PLK1抑制剂是否有效。在其他实施方案中,从患者体内取出癌细胞(例如,在血液、淋巴、骨髓或组织诸如活检组织或针抽吸(needle aspiration)中的癌细胞),并且将这些细胞在体外用PLK1抑制剂处理。这样的样品可以是任何存在癌症的组织或体液。
在这些方法中评估的癌细胞可以位于患者的组织或液体中,例如,携带下文鉴定的任何癌症的任何液体或组织,例如,患者的血液、组织抽吸物、骨髓、尿液等。在癌症位于患者血液中的一些实施方案中,待用于评估PLK1抑制的细胞可以从患者的淋巴、骨髓或血液样品中采集。患者血液中的任何癌症都可以通过这些方法评估。在一些实施方案中,癌症是急性髓系白血病(AML)、B细胞淋巴瘤或来自转移性肿瘤。评估来自血液中转移性肿瘤的细胞的方法是本领域已知的。参见,例如,Racila等人,1998。
这些方法不狭窄地限于在用PLK1抑制剂处理之后采集样品并评估PLK1靶的磷酸化的抑制的任何特定时间。可以在无需过度实验的情况下确定处理之后针对任何PLK1靶和PLK1抑制剂处理采集样品的时间间隔。在PLK1抑制剂是onvansertib(口服施用,半衰期约24小时)且PLK1靶是TCTP的情况下,认为可以在处理之后1至24小时的任何时间采集样品并进行评估。在一些实施方案中,PLK1靶的磷酸化在处理之后至少两小时确定。在其他实施方案中,PLK1靶的磷酸化在处理之后至少约3小时确定。
这种方法可以用于任何癌症细胞。示例性癌症包括但不限于急性成淋巴细胞白血病、AML、肾上腺皮质癌、肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、儿童小脑星形细胞瘤(childhood cerebellar astrocytoma)、儿童大脑星形细胞瘤(childhood cerebral astrocytoma)、基底细胞癌、皮肤癌(非黑素瘤)、肝外胆管癌、膀胱癌(bladder cancer)、骨癌、骨肉瘤和恶性纤维组织细胞瘤、脑肿瘤、脑干胶质瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤(supratentorial primitive neuroectodermal tumors)、视觉通路和下丘脑胶质瘤、乳腺癌、支气管腺瘤/类癌、类癌肿瘤、胃肠道癌症、中枢神经系统淋巴瘤、宫颈癌、儿童期癌症、慢性淋巴细胞白血病、慢性髓细胞白血病、慢性骨髓增生性紊乱、结肠癌、结肠直肠癌、皮肤T细胞淋巴瘤、蕈样肉芽肿、Sezary综合征、子宫内膜癌、食管癌、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、眼癌、眼内黑素瘤、视网膜母细胞瘤、胆囊癌(gallbladdercancer)、胃(胃)癌(gastric(stomach)cancer)、胃肠道类癌肿瘤、胃肠道间质肿瘤(GIST)、生殖细胞肿瘤、卵巢生殖细胞肿瘤、妊娠滋养层肿瘤胶质瘤、头颈癌、肝细胞(肝)癌、霍奇金淋巴瘤(Hodgkin lymphoma)、下咽癌、眼内黑素瘤、胰岛细胞肿瘤(内分泌胰腺)、卡波西肉瘤(Kaposi Sarcoma)、肾(肾细胞)癌(kidney(renal cell)cancer)、肾癌(renal cancer)、肾癌(kidney cancer)、喉癌(laryngeal cancer)、急性成淋巴细胞白血病、急性髓系白血病、慢性淋巴细胞白血病、慢性髓细胞白血病、毛细胞白血病、唇和口腔癌症、肝癌、肺癌、非小细胞肺癌、小细胞肺癌、AIDS相关淋巴瘤、非霍奇金淋巴瘤(non-Hodgkin lymphoma)、原发性中枢神经系统淋巴瘤、Waldenstrom巨球蛋白血症、髓母细胞瘤、黑素瘤、眼内(眼)黑素瘤、默克尔细胞癌、恶性间皮瘤、间皮瘤、转移性鳞状颈部癌、口癌、多发性内分泌肿瘤综合征(multiple endocrine neoplasia syndrome)、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常/骨髓增生性疾病、慢性髓细胞白血病、急性髓系白血病、多发性骨髓瘤、慢性骨髓增生性紊乱、鼻咽癌、神经母细胞瘤、口癌(oral cancer)、口腔癌(oral cavity cancer)、口咽癌(oropharyngeal cancer)、卵巢癌、卵巢上皮癌、卵巢低恶性潜能肿瘤、胰腺癌、胰岛细胞胰腺癌、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌(pharyngeal cancer)、嗜铬细胞瘤、成松果体细胞瘤和幕上原始神经外胚层肿瘤、垂体肿瘤、浆细胞瘤/多发性骨髓瘤、胸膜肺母细胞瘤、前列腺癌、直肠癌、肾盂和输尿管、移行细胞癌(renal pelvis and ureter,transitional cell cancer)、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、尤文肉瘤家族肿瘤(Ewing family of sarcoma tumors)、卡波西肉瘤(Kaposi Sarcoma)、软组织肉瘤、子宫肉瘤、皮肤癌(非黑素瘤)、皮肤癌(黑素瘤)、默克尔细胞皮肤癌、小肠癌、软组织肉瘤、鳞状细胞癌、胃(胃)癌(stomach(gastric)cancer)、幕上原始神经外胚层肿瘤、睾丸癌、喉癌、胸腺瘤、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行细胞癌、妊娠滋养层肿瘤、尿道癌、子宫内膜子宫癌、子宫肉瘤、阴道癌、外阴癌和威尔姆肿瘤(Wilm's Tumor)。
在一些实施方案中,与非癌细胞相比,癌症具有升高的PLK1活性。这样的癌症的非限制性实例包括卵巢癌、乳腺癌、结肠癌、肺癌、胰腺癌、前列腺癌、皮肤癌、鳞状细胞癌、淋巴谱系造血肿瘤、髓系造血肿瘤、中枢或外周神经系统肿瘤、急性髓系白血病、B细胞淋巴瘤、肾上腺皮质癌、食管癌、胃癌以及头颈癌。
在具体实施方案中,癌症是AML。在不同的实施方案中,患者具有骨髓增生异常综合征。
在一些实施方案中,在用PLK抑制剂处理之前的第一次确定之后,将确定的PLK1活性与正常的,即非癌性的PLK1活性进行比较,并且除非癌症中PLK1活性升高,否则患者或癌症样品不用PLK1抑制剂处理。这些实施方案的基本原理是PLK1抑制剂处理最有可能使患有具有升高的PLK1活性的癌症的患者受益。在一些实施方案中,如果PLK1活性低于正常,则患者或癌症样品不用PLK1抑制剂处理。
如本文使用的,“正常”PLK1活性是非癌细胞中的PLK1活性,无论是来自患者还是群体中的平均值,优选地与癌组织匹配或相似的组织或细胞中的PLK1活性。
任何PLK1抑制剂都可以使用这些方法评估。非限制性实例包括onvansertib、BI2536、volasertib(BI 6727)、GSK461364、HMN-176、HMN-214、AZD1775、CYC140、rigosertib(ON-01910)、MLN0905、TKM-080301、TAK-960或Ro3280。在一些实施方案中,PLK1抑制剂是onvansertib。在这些实施方案的一些中,癌症是AML。
PLK1靶(例如,TCTP)的磷酸化可以通过本领域已知的任何方法来确定。在一些实施方案中,磷酸化通过免疫化学确定,例如,使用(a)与未磷酸化的靶结合以及(b)与磷酸化的靶结合但与未磷酸化的靶不结合的抗体。这些方法不狭窄地限于任何特定的免疫化学方法。可以利用的方法的实例包括蛋白印迹(如下文的实施例1)、斑点印迹、ELISA、免疫组织化学和免疫PCR(用于pTCTP检测)。
免疫PCR类似于ELISA,不同的是寡核苷酸而不是酶是信号产生部分。来自寡核苷酸的信号通过聚合酶链式反应(PCR)扩增产生。因为PCR将寡核苷酸扩增许多倍,通常产生染料标记的扩增产物,所以免疫PCR非常灵敏,并且当用于本方法时,能够检测非常少量的磷酸化的TCTP。
因为免疫PCR类似于ELISA,所以免疫PCR可以使用本领域已知的任何固相(例如,微量滴定板、珠等)以已经描述为用ELISA检测其他蛋白的任何形式(例如直接、间接、夹心或竞争形式)用于检测pTCTP(例如,参见,BioRad,2017)。
用于检测pTCTP的免疫PCR的非限制性实例的图提供于图10中。在该实例中,抗生物素蛋白被共价或非共价结合至固相。与磷酸化的TCTP(“pTCTP”)上的第一表位(“表位-1”)结合的生物素标记的TCTP捕获抗体与抗生物素蛋白结合。添加疑似具有pTCTP的样品,然后添加TCTP报告物抗体。在这种分析中,捕获抗体或报告物抗体都可以与pTCTP结合,但不能与未磷酸化的TCTP结合。在一些实施方案中,报告物抗体可以与pTCTP结合,但不能与未磷酸化的TCTP结合。双链DNA分子(dsDNA)位于报告物抗体上。然后进行扩增dsDNA的PCR。仅当样品具有pTCTP时,才会存在PCR产物;该PCR产物的量与样品中的pTCTP产物的量成比例。然后可以对PCR产物进行定量,以确定存在于样品中的pTCTP的量。
在以上任何方法中,可以测量靶蛋白任何氨基酸残基的磷酸化。例如,用靶TCTP,可以测量丝氨酸46或苏氨酸65或二者的磷酸化。
这些方法可以用于确定PLK1抑制剂对癌症的有效性。这在下文实施例1中得到证实,其中PLK1抑制剂onvansertib抑制对onvansertib有响应的患者中AML细胞中的PLK1靶TCTP的磷酸化,但不抑制对onvansertib没有响应的患者中的AML细胞中的PLK1靶TCTP的磷酸化。
本发明还包括以上方法的某些变化。例如,,可以评估患者血清中的无细胞PLK1和/或PLK1靶(例如,TCTP)当暴露于PLK1抑制剂时靶磷酸化的抑制,而不是评估癌细胞中的PLK1抑制。对于这种变化,可以利用非常灵敏的方法,例如免疫PCR,来确定磷酸化的抑制。
在另外的变化中,PLK1抑制剂抑制癌症中PLK1的能力可以通过使用本文描述的方法确定PLK1抑制剂抑制癌症中PLK1活性的能力来确定。
如下文实施例中证实的,PLK1抑制剂对PLK1靶磷酸化的抑制表明PLK1抑制剂对癌症有效。因此,这些方法可以用于早期确定PLK1抑制剂是否有效。
表明特定PLK1抑制剂的有效性的PLK1靶磷酸化抑制百分比的确定可以在无需过度实验的情况下进行,并且取决于PLK1靶、PLK1抑制剂、处理之后采集样品进行测试的时间、如何测量处理的有效性以及所期望的假阳性或假阴性的相对数目。例如,在下文实施例中,当抑制百分比设定为50%时,存在一个假阴性(图9B中加星号的条),其中pTCTP的抑制仅为40%,但是PLK1抑制剂处理引起该患者中骨髓母细胞%的大幅降低和客观响应。如果抑制百分比设定为35%,就不会存在假阴性。因此,表明PLK1抑制剂处理的有效性的抑制百分比可以设定为任何百分比,例如,30%、35%、40%、45%、50%、55%或60%,或任何其他百分比。
因此,在一些实施方案中,处理之后PLK1靶的磷酸化降低至少30%、35%、40%、45%、50%、55%或60%表明处理有效。
以上方法可以用于鉴定PLK1抑制剂针对癌症的功效的试验中的候选药物。在该申请的一些实施方案中,如果处理之后PLK1靶的磷酸化相对于处理之前TCTP的磷酸化没有被降低至少30%、35%、40%、45%、50%、55%或60%,则患者没有资格参与试验。
以上描述的PLK1抑制剂处理有效性的确定可以用于决定是否用PLK1抑制剂治疗性处理(therapeutically treat)患者,其中如果PLK1靶的磷酸化降低百分比高于如以上描述设定的阈值,则患者仅用PLK1抑制剂处理。因此,在一些实施方案中,仅在处理之后TCTP的磷酸化相对于处理之前TCTP的磷酸化被降低至少30%、35%、40%、45%、50%、55%或60%时,患者才用PLK1抑制剂进行治疗性处理。
当单独的PLK1抑制剂用于治疗癌症时,或者当患者也正在用PLK1抑制剂联合一种或更多种非PLK1抑制剂的抗肿瘤剂治疗或考虑用PLK1抑制剂联合一种或更多种非PLK1抑制剂的抗肿瘤剂治疗癌症时,可以使用这些方法。这样的抗癌剂的非限制性实例是顺铂、阿糖胞苷、地西他滨、多柔比星、吉西他滨、紫杉醇、SN38、索拉非尼、万珂、阿比特龙、依鲁替尼、阿卡替尼、阿扎胞苷、维奈托克、CPT11、5FU、贝伐单抗、硼替佐米、组蛋白脱乙酰酶抑制剂。在各种实施方案中,无论患者是否用PLK1抑制剂进行治疗性处理,患者都继续用抗癌剂处理。
在一些实施方案中,癌症是急性髓系白血病(AML),并且患者也正在用以下处理或考虑用以下处理:阿糖胞苷、阿扎胞苷、维奈托克、地西他滨、FLT3抑制剂或其组合(单独的或与PLK1抑制剂组合)。
在其他实施方案中,癌症是非霍奇金淋巴瘤,并且患者也正在用以下处理或考虑用以下处理:组蛋白脱乙酰化酶抑制剂、依鲁替尼、阿卡替尼、维奈托克或其组合。
在另外的实施方案中,癌症是去势耐受性或去势敏感性前列腺癌,并且患者也正在用以下处理或考虑用以下处理:阿比特龙、抗雄激素或其组合。
在另外的实施方案中,癌症是腺癌,例如,胰腺腺癌、乳腺腺癌或结肠腺癌,并且患者也正在用以下处理或考虑用以下处理:紫杉醇、索拉非尼、硼替佐米、顺铂、SN38、CPT11、5FU、贝伐单抗、吉西他滨或其组合。
在其他实施方案中,癌症是早幼粒细胞白血病,并且患者也正在用以下处理或考虑用以下处理:紫杉醇、多柔比星、阿糖胞苷或其组合。
在另外的实施方案中,癌症是多发性骨髓瘤,并且患者也正在用以下处理或考虑用以下处理:卡非佐米、伊沙佐米、硼替佐米、沙利度胺、来那度胺、泊马度胺、皮质类固醇或其组合。
在另外的实施方案中,患者具有骨髓增生异常综合征(MDS),并且患者也正在用以下处理或考虑用以下处理:阿糖胞苷、阿扎胞苷、维奈托克、地西他滨、FLT3抑制剂或其组合。
本文还提供了一种方法,所述方法包括通过测量没有用polo样激酶1(PLK1)抑制剂处理的情况下的PLK1靶的磷酸化来确定患者癌症中的PLK1活性。在一些实施方案中,将PLK1活性与正常活性相比较。
这些方法允许在任何PLK1抑制剂处理之前评估癌症中PLK1活性的水平。在一些实施方案中,如果癌症中的PLK1活性升高,则患者用PLK1抑制剂处理,并且如果癌症中的PLK1活性没有升高,则患者不用PLK1抑制剂处理。在其他实施方案中,如果癌症中的PLK1活性升高或正常,则患者用PLK1抑制剂处理,并且如果癌症中的PLK1活性低于正常,则患者不用PLK1抑制剂处理。
在这些方法的各种实施方案中,如果患者或样品用PLK1抑制剂处理,则癌症中的PLK1活性通过本文描述的任何方法来确定。
优选的实施方案被描述在以下的实施例中。通过考虑本文公开的说明书或本发明的实践,落在本文的权利要求书的范围内的其他实施方案对于本领域技术人员将是明显的。预期说明书连同实施例一起被认为仅为示例性的,本发明的范围和精神由在实施例后所附的权利要求指示。
实施例1.onvansertib对翻译控制肿瘤蛋白(TCTP)磷酸化的抑制预测急性髓系白
血病对polo样激酶1(PLK1)抑制剂处理的响应
介绍
本研究旨在确定PLK1抑制剂onvansertib对患者血液中AML细胞中TCTP磷酸化的抑制是否预测onvansertib处理对AML的功效。数据表明,onvansertib抑制AML细胞的TCTP磷酸化确实预测AML对onvansertib处理的响应。
材料和方法
本文提供的患者数据来自临床试验NCT03303339“Onvansertib in CombinationWith Either Low-dose Cytarabine(LDAC)or Decitabine in Adult Patients WithAcute Myeloid Leukemia(AML)(Onvansertib联合低剂量阿糖胞苷(LDAC)或地西他滨处理患有成人急性髓系白血病(AML)的成人患者)(ClinicalTrials.gov)”中的患者。
血液中TCTP丝氨酸46磷酸化的确定如下。根据制造商的建议,使用Leucosep离心管(VWR)和Histopaque-1077(Sigma)从Cellsave血液管(Menarini Silicon Biosystems)中分离外周血单核细胞(PBMC)。
使用具有150mM NaCl和1×蛋白酶和磷酸酶抑制剂混合物(ThermoFisher)的M-PER缓冲液(ThermoFisher)从PBMC和细胞系制备蛋白提取物。蛋白浓度用Pierce BCA蛋白测定试剂盒(ThermoFisher)测量。
按照制造商的方案,使用Wes系统(ProteinSimple)(毛细管电泳和免疫检测技术的组合)以Simple WesternTM测定进行蛋白印迹分析。简言之,将具有等蛋白浓度的提取物与0.1×样品缓冲液和5×荧光主混合物混合。将变性蛋白样品、生物素化梯状条带(ProteinSimple)、初级抗体、辣根过氧化物酶(HRP)-缀合的二级抗体(ProteinSimple)、化学发光底物和洗涤缓冲液分配到测定板的相应孔中,并置于Wes设备中。初级抗体购自CellSignaling Technology:磷酸-TCTP-Ser46(#5251)和TCTP(#5128),并且以1:50的浓度使用。使用Compass软件(ProteinSimple)进行定量分析。pTCTP的信号强度(面积)被归一化为TCTP峰面积,并且报告为pTCTP%。
患者中的PLK1抑制在施用峰浓度(C最大)的onvansertib后3小时采集的血液中进行评估。
响应者被定义为显示处理期间循环和骨髓母细胞减少的患者。
结果
用onvansertib联合低剂量阿糖胞苷(LDAC)或地西他滨处理的6名患者中的3名表现出对处理有响应,如通过血液(图1A)和骨髓(图1B)中的白血病细胞百分比的减少显示的,其中2名患者(07-009和07-011)在骨髓中具有分别从96%至55%和55%至15%的减少。
如果在体内有效抑制PLK1,则onvansertib应如图2A中示出的防止TCTP磷酸化,特别地因为onvansertib在体外以剂量依赖性方式抑制pTCTP(图2B)。
将AML细胞系MV4-11和HL-60用onvansertib(PCM-075)(0.1μM或0.5μM)、阿糖胞苷(10nM或100nM)或地西他滨(0.2μM或1μM)处理15分钟。然后从细胞中提取蛋白并评估pTCTP。如图2C中示出的,onvansertib,而不是阿糖胞苷或地西他滨,抑制pTCTP。
图3A示出了三名施用onvansertib和LDAC(阿糖胞苷)的患者血液中白血病细胞的百分比。患者01-002对处理有响应,而其他两名患者没有响应。如图3B中示出的,仅响应者显示出pTCTP的减少,早在处理开始后三小时显示。
图4A示出了三名施用onvansertib和地西他滨的患者血液中白血病细胞的百分比。患者07-009和07-011二者都对处理有响应,而患者07-013没有响应。如图3B中示出的,仅两名响应者显示出pTCTP的减少,都早在三小时显示。
图3和图4中的数据显示,使用本文描述的TCTP磷酸化方法,可以在开始处理的5天内鉴定响应者,而通过确定血液中白血病细胞%,直到15天或更长时间才能够鉴定响应者。
图5示出了图3和图4的蛋白印迹的定量。响应者可以在蛋白印迹中容易地鉴定。
为了确定较高剂量的onvansertib是否能够降低无响应者中的pTCTP,对施用18mg/m2的患者的血细胞进行分析。图6示出了图3和图4中描述的6名以12mg/m2处理的患者的蛋白印迹,连同5名以较高剂量处理的响应者的蛋白印迹。即使在较高剂量的onvansertib,无响应者的细胞也没有显示出对处理有响应的pTCTP的减少。
分析有响应者和无响应者中的pTCTP水平,以确定onvansertib处理前以及处理后的差异。如图7中示出,处理前pTCTP水平不存在差异。处理后响应者中pTCTP的减少相比于无响应者中pTCTP的减少显著更高。
实施例2.onvansertib对TCTP磷酸化的抑制预测急性髓系白血病对polo样激酶1
(PLK1)抑制剂处理的响应
实施例1中描述的方法用于确定增加的剂量的onvansertib处理抑制TCTP磷酸化的能力,以及使用该抑制来预测疾病对该处理的响应性的能力。
从实施例1中描述的试验中募集的患者在onvansertib处理之前以及处理之后3小时采集血液样品。onvansertib处理为12mg/m2、18mg/m2、27mg/m2或40mg/m2。pTCTP和TCTP通过蛋白印迹评估,并且定量%pTCTP(pTCTP/TCTP)。
在这些研究中,生物标志物阳性被定义为从T=0至T=3h,%pTCTP减少≥50%。
结果示于图8中。上图和中图分别示出了来自具有生物标志物阳性和生物标志物阴性pTCTP抑制的患者中的样品的蛋白印迹的实例。24名可评估患者中的9名(38%)是生物标志物阳性的。生物标志物阳性不依赖于onvansertib剂量、药代动力学,也不依赖于LDAC或地西他滨的单剂效应。
在生物标志物阳性的患者中,01-002和08-027正在用LDAC处理;07-009、05-030和07-036正在用地西他滨处理。在生物标志物阴性的患者中,07-018和07-033用LDAC处理;07-004、01-024和12-041用地西他滨处理。这确认了用LDAC或地西他滨处理明显不影响PLK1抑制剂(此处为onvansertib)抑制PLK1靶(此处为TCTP)磷酸化的能力。
生物标志物阳性患者正在用onvansertib 12mg/m2、27mg/m2或40mg/m2处理,并且生物标志物阴性患者正在用onvansertib 12mg/m2、18mg/m2、27mg/m2和40mg/m2处理。这表明生物标志物阳性不依赖于onvansertib剂量。此外,药代动力学分析显示生物标志物阳性与血液中onvansertib浓度之间没有相关性。
图8的下图示出了生物标志物阳性(“靶参与(No Target Engagement)”)患者和生物标志物阴性(“无靶参与(No Target Engagement)”)患者在剂量后时相对于剂量前的%pTCTP范围。
图9A和图9B示出生物标志物阳性预测对处理的响应。图9A示出了,生物标志物阳性患者与生物标志物阴性患者相比具有显著更大的BM母细胞的减少。如图9B中示出,9名生物标志物阳性患者中的6名具有≥50%的BM母细胞的减少。4名患者具有完全响应[CR]或具有不完全血液学恢复的CR[CRi],如根据Cheson等人(2003)中定义的。在4名具有客观响应(CR+CRi)的患者中,3名是生物标志物阳性的,且1名具有40%的pTCTP下降。
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鉴于以上所述,将会看到,本发明的几个目的得以实现,并且获得了其他优点。
由于可以在不脱离本发明的范围的情况下对上述方法和组合物进行各种改变,因此意图是上述描述中包含的和附图中示出的所有内容都应被解释为说明性的,而不是限制性的。
在本说明书中引用的所有参考文献都在此通过引用并入。本文对参考文献的讨论仅意图在总结作者的主张,并不承认任何参考文献构成现有技术。申请人保留质疑所引用的参考文献的准确性和针对性的权利。
Claims (61)
1.一种方法,所述方法包括:
通过在以下时间测量PLK1靶的磷酸化来确定患者癌症中的PLK1活性:
(a)在用polo样激酶1(PLK1)抑制剂处理(i)患者或(ii)来自所述患者的癌症样品之前,以及
(b)处理之后。
2.根据权利要求1所述的方法,其中PLK1活性通过翻译控制肿瘤蛋白(TCTP)的磷酸化来测量。
3.根据权利要求1所述的方法,其中用所述PLK1抑制剂处理患者。
4.根据权利要求1所述的方法,其中用所述PLK1抑制剂处理从患者中取出的癌症样品。
5.根据权利要求4所述的方法,其中所述癌症样品是血液样品。
6.根据权利要求4所述的方法,其中所述癌症样品是组织样品。
7.根据权利要求1所述的方法,其中所述PLK1靶在患者的淋巴、骨髓或血液样品中。
8.根据权利要求1所述的方法,其中所述PLK1靶在所述癌症的细胞中。
9.根据权利要求1所述的方法,其中所述PLK1靶在所述患者的血液中是无细胞的。
10.根据权利要求1所述的方法,其中所述癌症是卵巢癌、乳腺癌、结肠癌、肺癌、胰腺癌、前列腺癌、皮肤癌、鳞状细胞癌、淋巴谱系造血肿瘤、髓系造血肿瘤、中枢或外周神经系统肿瘤、急性髓系白血病、B细胞淋巴瘤、肾上腺皮质癌、食管癌、胃癌或头颈癌。
11.根据权利要求1所述的方法,其中所述癌症是急性髓系白血病(AML)、B细胞淋巴瘤或来自转移性肿瘤。
12.根据权利要求1所述的方法,其中所述癌症是AML。
13.根据权利要求1所述的方法,其中所述患者具有骨髓增生异常综合征。
14.根据权利要求1所述的方法,其中除非所述癌症中的PLK1活性升高,否则所述患者或癌症样品不用所述PLK1抑制剂处理。
15.根据权利要求1所述的方法,其中如果PLK1活性低于正常,则所述患者或癌症样品不用所述PLK1抑制剂处理。
16.根据权利要求1所述的方法,其中所述PLK1抑制剂是onvansertib、BI2536、volasertib(BI 6727)、GSK461364、HMN-176、HMN-214、AZD1775、CYC140、rigosertib(ON-01910)、MLN0905、TKM-080301、TAK-960或Ro3280。
17.根据任何权利要求1所述的方法,其中所述PLK1抑制剂是onvansertib。
18.根据权利要求1所述的方法,其中所述PLK1靶的磷酸化通过免疫化学测量。
19.根据权利要求18所述的方法,其中所述免疫化学测量是通过蛋白印迹。
20.根据权利要求18所述的方法,其中所述免疫化学测量是通过固相免疫测定。
21.根据权利要求2所述的方法,其中TCTP的磷酸化通过免疫PCR测量。
22.根据权利要求2所述的方法,其中测量TCTP丝氨酸46的磷酸化。
23.根据权利要求2所述的方法,其中测量TCTP苏氨酸65的磷酸化。
24.根据权利要求1所述的方法,其中处理之后所述PLK1靶的磷酸化降低至少35%表明所述处理是有效的。
25.根据权利要求24所述的方法,其中处理之后所述PLK1靶的磷酸化降低至少50%表明所述处理是有效的。
26.根据权利要求1所述的方法,其中所述PLK1靶的磷酸化在处理之后至少两小时确定。
27.根据权利要求1所述的方法,其中所述PLK1靶的磷酸化在处理之后至少约三小时确定。
28.根据权利要求1-27中任一项所述的方法,其中所述患者是参与所述PLK1抑制剂针对所述癌症的功效试验的候选人,
其中如果处理之后所述PLK1靶的磷酸化相对于处理之前TCTP的磷酸化没有被降低至少35%,则所述患者没有资格参与所述试验。
29.根据权利要求1-27中任一项所述的方法,其中所述患者是参与所述PLK1抑制剂针对所述癌症的功效的试验的候选人,
其中如果处理之后TCTP的磷酸化相对于处理之前TCTP的磷酸化没有被降低至少50%,则所述患者没有资格参与所述试验。
30.根据权利要求1-27中任一项所述的方法,其中仅在处理之后TCTP的磷酸化相对于处理之前TCTP的磷酸化被降低至少35%时,所述患者才用所述PLK1抑制剂进行治疗性处理。
31.根据权利要求1-27中任一项所述的方法,其中仅在处理之后TCTP的磷酸化相对于处理之前TCTP的磷酸化被降低至少50%时,所述患者才用所述PLK1抑制剂进行治疗性处理。
32.根据权利要求30所述的方法,其中用所述PLK1抑制剂治疗性处理的患者还用顺铂、阿糖胞苷、地西他滨、多柔比星、吉西他滨、紫杉醇、SN38、索拉非尼、万珂、阿比特龙、依鲁替尼、阿卡替尼、阿扎胞苷、维奈托克、CPT11、5FU、贝伐单抗、硼替佐米、组蛋白脱乙酰酶抑制剂或其组合处理。
33.根据权利要求30所述的方法,其中,如果所述患者未用所述PLK1抑制剂处理,则所述患者用顺铂、阿糖胞苷、地西他滨、多柔比星、吉西他滨、紫杉醇、SN38、索拉非尼、万珂、阿比特龙、依鲁替尼、阿卡替尼、阿扎胞苷、维奈托克、CPT11、5FU、贝伐单抗、硼替佐米、组蛋白脱乙酰酶抑制剂或其组合处理。
34.根据权利要求30所述的方法,其中,所述患者无论是否用所述PLK1抑制剂处理,所述患者都用顺铂、阿糖胞苷、地西他滨、多柔比星、吉西他滨、紫杉醇、SN38、索拉非尼、万珂、阿比特龙、依鲁替尼、阿卡替尼、阿扎胞苷、维奈托克、CPT11、5FU、贝伐单抗、硼替佐米、组蛋白脱乙酰酶抑制剂或其组合处理。
35.根据权利要求30所述的方法,其中所述患者具有急性髓系白血病。
36.根据权利要求35所述的方法,其中所述患者正在用阿糖胞苷、阿扎胞苷、维奈托克、地西他滨、FLT3抑制剂或其组合处理。
37.根据权利要求30所述的方法,其中所述患者具有非霍奇金淋巴瘤。
38.根据权利要求37所述的方法,其中所述患者正在用组蛋白脱乙酰酶抑制剂、依鲁替尼、阿卡替尼、维奈托克或其组合处理。
39.根据权利要求30所述的方法,其中所述患者具有前列腺癌。
40.根据权利要求39所述的方法,其中所述患者正在用阿比特龙、抗雄激素或其组合处理。
41.根据权利要求39所述的方法,其中所述前列腺癌是去势耐受性的,并且所述患者正在用阿比特龙处理。
42.根据权利要求30所述的方法,其中所述癌症是腺癌。
43.根据权利要求42所述的方法,其中所述患者正在用紫杉醇、索拉非尼、硼替佐米、顺铂、SN38、CPT11、5FU、贝伐单抗、吉西他滨或其组合处理。
44.根据权利要求42所述的方法,其中所述腺癌是胰腺腺癌、乳腺腺癌或结肠腺癌。
45.根据权利要求30所述的方法,其中所述癌症是早幼粒细胞白血病。
46.根据权利要求45所述的方法,其中所述患者正在用紫杉醇、多柔比星、阿糖胞苷或其组合处理。
47.根据权利要求30所述的方法,其中所述癌症是多发性骨髓瘤。
48.根据权利要求47所述的方法,并且所述患者正在用卡非佐米、伊沙佐米、硼替佐米、沙利度胺、来那度胺、泊马度胺、皮质类固醇或其组合处理。
49.根据权利要求30所述的方法,其中所述患者具有骨髓增生异常综合征。
50.根据权利要求49所述的方法,其中所述患者正在用阿扎胞苷、地西他滨或其组合处理。
51.根据权利要求1所述的方法,其中
所述癌症是急性髓系白血病(AML);
所述PLK1靶是翻译控制肿瘤蛋白(TCTP);
所述患者用所述PLK1抑制剂处理;
并且
测量在处理之前以及之后采集的患者血液样品中TCTP的磷酸化。
52.根据权利要求51所述的方法,其中测量TCTP的丝氨酸46的磷酸化。
53.根据权利要求51所述的方法,其中所述PLK1抑制剂是onvansertib。
54.根据权利要求51所述的方法,其中TCTP的磷酸化通过免疫化学测量。
55.根据权利要求54所述的方法,其中所述免疫化学测量是通过蛋白印迹。
56.根据权利要求54所述的方法,其中所述免疫化学测量是通过免疫PCR。
57.根据权利要求51-56中任一项所述的方法,其中
所述患者正在用阿糖胞苷、阿扎胞苷、维奈托克、地西他滨、FLT3抑制剂或其组合处理;并且
仅在处理之后TCTP的磷酸化相对于处理之前TCTP的磷酸化被降低至少35%时,才用所述PLK1抑制剂处理所述患者。
58.一种方法,所述方法包括:
通过测量没有用polo样激酶1(PLK1)抑制剂处理的情况下PLK1靶的磷酸化来确定患者癌症中的PLK1活性。
59.根据权利要求58所述的方法,其中,
如果所述癌症中的PLK1活性升高,则所述患者用PLK1抑制剂处理,并且
如果所述癌症中的PLK1活性没有升高,则所述患者不用PLK1抑制剂处理。
60.根据权利要求58所述的方法,其中,
如果所述癌症中的PLK1活性升高或正常,则所述患者用PLK1抑制剂处理,并且
如果所述癌症中的PLK1活性低于正常,则所述患者不用PLK1抑制剂处理。
61.根据权利要求59或60所述的方法,其中,
如果所述患者用PLK1抑制剂处理,则所述癌症中的PLK1活性通过权利要求1-27中任一项所述的方法来确定。
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