CN110291104B - 具有针对携带egfr或her2外显子20突变之癌细胞的抗肿瘤活性的化合物 - Google Patents
具有针对携带egfr或her2外显子20突变之癌细胞的抗肿瘤活性的化合物 Download PDFInfo
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Abstract
本公开内容提供了通过施用第三代酪氨酸激酶抑制剂(例如波齐替尼或阿法替尼)来在被确定具有EGFR和/或HER2外显子20突变(例如插入突变)的患者中治疗癌症的方法。
Description
本申请要求于2016年11月17日提交的美国临时专利申请No.62/423,732、2016年11月29日提交的美国临时申请号62/427,692和2017年10月16日提交的美国临时申请号62/572,716的权益,其各自的全部内容通过引用并入本文。
包含在4KB(在Microsoft Windows中测量的)的并且于2017年11月17日创建的名为“UTFCP1306WO.txt”的文件中的序列表通过电子提交随同提交,并且通过引用并入本文。
背景
本发明在由国立卫生研究院(National Institutes of Health)授予的基金号CA190628的政府支持下完成。政府对本发明具有某些权利。
1.技术领域
本发明一般地涉及分子生物学和医学领域。更具体地,其涉及治疗具有EGFR和/或HER2外显子20突变(例如插入突变)的患者的方法。
2.背景技术
大约10%至15%的NSCLC具有激活的EGFR突变。对于其肿瘤具有“经典的”敏感突变(L858R和外显子19缺失)的这些患者的大多数,TKI(例如吉非替尼(gefitinib)和厄洛替尼(erlotinib))与单独的化学治疗相比提供显著的临床益处,其中约70%经历客观响应(objective response,OR)、改善的无进展存活(progression free survival,PFS)和生活质量(Maemondo et al.,2010)。然而,大约10%至12%的EGFR突变体NSCLC肿瘤在EGFR的外显子20内具有框内插入(Arcila et al.,2012),并且通常对EGFR TKI具有抗性。此外,NSCLC中90%的HER2突变是外显子20突变(Mazieres et al.,2013)。EGFR和HER2外显子20突变一起占NSCLC患者的约4%。迄今为止的数据表明,HER2的可用TKI(阿法替尼(afatinib)、拉帕替尼(lapatinib)、奈拉替尼(neratinib)、达克替尼(dacomitinib))在患有HER2突变体肿瘤的患者中具有有限的活性,其中许多研究报道OR率低于40%(Kosaka etal.,2017),尽管在用阿法替尼治疗的HER2小鼠模型中观察到一些临床前活性(Perera etal.,2009)。
EGFR和HER2的外显子20包含两个主要区域,c-螺旋(EGFR中第762至766位残基和HER2中第770至774位残基)和c-螺旋之后的环(EGFR中第767至774位残基和HER2中第775至783位残基)。EGFR外显子20插入D770insNPG的晶体学已显示在第764位残基之后的插入中诱导针对第一代TKI之抗性的稳定且脊状的活性构象。然而,EGFRA763insFQEA的建模示出在第764位残基之前的插入没有表现出这种作用并且不诱导药物抗性(Yasuda et al.,2013)。此外,在其中插入是在c-螺旋之后的环中的EGFR外显子20驱动之NSCLC(EGFRH773insNPH)的患者来源的异种移植物(patient derived xenograft,PDX)模型中,发现第三代EGFR TKI奥希替尼(osimertinib)(AZD9291)和罗西替尼(rociletinib)(CO-1696)具有最小活性(Yang et al.,2016)。在稀有的EGFR和HER2外显子20突变的最近的研究中,作者发现了对基于共价喹唑啉的第二代抑制剂(例如达克替尼和阿法替尼)的不均一响应;然而,靶向更常见的外显子20插入突变所需的浓度高于临床上可达到的浓度(Kosaka etal.,2017)。因此,对鉴定克服具有在EGFR和HER2中的外显子20突变(特别是插入突变)的NSCLC肿瘤的固有药物抗性的新治疗存在显著的临床需求。
发明内容
本公开内容提供了用于在具有EGFR和/或HER2外显子20突变(例如外显子20插入突变)的患者中治疗癌症的方法和组合物。在一个实施方案中,提供了在对象中治疗癌症的方法,其包括向所述对象施用有效量的波齐替尼(poziotinib),其中所述对象已被确定具有一个或更多个EGFR外显子20突变,例如一个或更多个EGFR外显子20插入突变。在一些特别的方面,对象是人。
在某些方面,一个或更多个EGFR外显子20突变包含第763至778位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在一些方面,对象已被确定具有2、3或4个EGFR外显子20突变。在一些方面,所述一个或更多个EGFR外显子20突变在选自A763、A767、S768、V769、D770、N771、P772和H773的一个或更多个残基处。在某些方面,对象已被确定不具有在残基C797处的EGFR突变。在一些方面,所述一个或更多个外显子20突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH和N771dupNPH。
在某些方面,通过分析来自对象的基因组样品,对象被确定具有EGFR外显子20突变,例如插入突变。在一些方面,基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。在一些特别的方面,通过核酸测序(例如,肿瘤组织或来自血浆的循环游离DNA的DNA测序)或PCR分析来确定EGFR外显子20突变的存在。
在某些方面,所述方法还包括施用另外的抗癌治疗。在一些方面,抗癌治疗是化学治疗、放射治疗、基因治疗、手术、激素治疗、抗血管生成治疗或免疫治疗。在某些方面,波齐替尼和/或抗癌治疗静脉内、皮下、骨内、经口、经皮、以持续释放、以受控释放、以延迟释放、作为栓剂或舌下施用。在一些方面,施用波齐替尼和/或抗癌治疗包括局部、区域或全身施用。在一些特别的方面,波齐替尼和/或抗癌治疗施用两次或更多次,例如每天、每隔一天或每周。
在一些方面,癌症是口腔癌、口咽癌、鼻咽癌、呼吸系统癌症、泌尿生殖系统癌症、胃肠癌、中枢或周围神经系统组织癌症、内分泌或神经内分泌癌或造血系统癌症、胶质瘤、肉瘤、上皮癌、淋巴瘤、黑素瘤、纤维瘤、脑脊膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌(biliary cancer)、嗜铬细胞瘤、胰岛细胞癌、利-弗劳梅尼肿瘤(Li-Fraumeni tumor)、甲状腺癌、甲状旁腺癌、垂体肿瘤、肾上腺肿瘤、成骨肉瘤肿瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头颈癌(head and neck cancer)、前列腺癌、食管癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌。在一些特别的方面,癌症是非小细胞肺癌。
在另一个实施方案中,提供了包含波齐替尼的药物组合物,其用于被确定具有一个或更多个EGFR外显子20突变(例如一个或更多个EGFR外显子20插入突变)的患者。在某些方面,所述一个或更多个EGFR外显子20突变包含第763至778位氨基酸之间3至18个核苷酸的点突变、插入和/或缺失。在某些方面,对象已被确定具有2、3或4个EGFR外显子20突变。
在一些方面,所述一个或更多个EGFR外显子20插入突变在选自A763、A767、S768、V769、D770、N771、P772和H773的一个或更多个残基处。在某些方面,对象已被确定不具有在残基C797处的EGFR突变。在一些特别的方面,所述一个或更多个外显子20突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH和N771dupNPH。在一些方面,患者正在用抗癌治疗进行治疗。
在另一个实施方案中,提供了在患有癌症的对象中预测对单独的或与抗癌治疗组合的波齐替尼的响应的方法,其包括检测获自所述患者的基因组样品中的EGFR外显子20突变(例如,EGFR外显子20插入突变),其中如果所述样品对于EGFR外显子20突变的存在呈阳性,则预测所述患者具有对单独的或与抗癌治疗组合的波齐替尼的有利响应。在一些方面,基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。在某些方面,通过核酸测序或PCR分析来确定EGFR外显子20突变的存在。在某些方面,EGFR外显子20突变包含第763至778位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在一些方面,EGFR外显子20突变在残基A763、H773、A767、S768、V769、D770、N771和/或D773处。在一些方面,EGFR外显子20突变选白A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH和N771dupNPH。在某些方面,对单独的或与抗癌治疗组合的波齐替尼抑制剂的有利响应包括减小肿瘤尺寸或负荷、阻断肿瘤生长、减轻肿瘤相关疼痛、减轻癌症相关病理状况、减轻癌症相关症状、癌症无进展、延长无疾病间隔、延长进展时间、诱导缓解、降低转移或延长患者存活。在另一些方面,向预期具有有利响应的患者施用单独的或与第二抗癌治疗组合的波齐替尼。
另一个实施方案提供了在患者中治疗癌症的方法,其包括向对象施用有效量的波齐替尼或阿法替尼,其中所述对象已被确定具有选自A775insV G776C、A775insYVMA、G776CV777insC、G776del insVV、G776del insVC和P780insGSP的一个或更多个HER2外显子20突变。在一些方面,一个或更多个HER2外显子20突变还包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在一些方面,所述一个或更多个HER2外显子20突变在残基A775、G776、S779和/或P780处。在一些特别的方面,对象是人。
在一些方面,所述方法还包括施用mTOR抑制剂。在某些方面,mTOR抑制剂是雷帕霉素、替西罗莫司(temsirolimus)、依维莫司(everolimus)、瑞达莫司(ridaforolimus)或MLN4924。在一些特别的方面,mTOR抑制剂是依维莫司。
在某些方面,波齐替尼或阿法替尼和/或mTOR抑制剂静脉内、皮下、骨内、经口、经皮、以持续释放、以受控释放、以延迟释放、作为栓剂或舌下施用。在一些方面,通过分析来自患者的基因组样品,患者被确定具有HER2外显子20突变。在某些方面,基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。在一些方面,通过核酸测序或PCR分析来确定HER2外显子20突变的存在。
在另外的方面,所述方法还包括施用另外的抗癌治疗。在一些方面,抗癌治疗是化学治疗、放射治疗、基因治疗、手术、激素治疗、抗血管生成治疗或免疫治疗。
在一些方面,癌症是口腔癌、口咽癌、鼻咽癌、呼吸系统癌症、泌尿生殖系统癌症、胃肠癌、中枢或周围神经系统组织癌症、内分泌或神经内分泌癌或造血系统癌症、胶质瘤、肉瘤、上皮癌、淋巴瘤、黑素瘤、纤维瘤、脑脊膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、利-弗劳梅尼肿瘤、甲状腺癌、甲状旁腺癌、垂体肿瘤、肾上腺肿瘤、成骨肉瘤肿瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头颈癌、前列腺癌、食管癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌。在某些方面,癌症是非小细胞肺癌。
在另一个实施方案中,提供了包含波齐替尼或阿法替尼的药物组合物,其用于被确定具有选自A775insV G776C、A775insYVMA、G776C V777insC、G776del insVV、G776delinsVC和P780insGSP的一个或更多个HER2外显子20突变的患者。在一些方面,HER2外显子20突变还包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在一些方面,HER2外显子20突变在残基A775、G776、S779和/或P780处。在一些方面,患者正在用抗癌治疗进行治疗。
在另一个实施方案中,提供了在患有癌症的患者中预测对单独的或与抗癌治疗组合的波齐替尼或阿法替尼的响应的方法,其包括检测获自所述患者的基因组样品中的选自A775insV G776C、A775insYVMA、G776C V777insC、G776del insVV、G776del insVC和P780insGSP的HER2外显子20突变(例如,HER2外显子20插入突变),其中如果所述样品对于HER2外显子20突变的存在呈阳性,则预测所述患者具有对单独的或与抗癌治疗组合的波齐替尼或阿法替尼的有利响应。在一些方面,HER2外显子20突变还包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在某些方面,HER2外显子20突变在残基A775、G776、S779和/或P780处。
在一些方面,基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。在某些方面,通过核酸测序或PCR分析来确定HER2外显子20突变的存在。在一些特别的方面,抗癌治疗是mTOR抑制剂。在一些方面,对单独的或与抗癌治疗组合的波齐替尼或阿法替尼抑制剂的有利响应包括减小肿瘤尺寸或负荷、阻断肿瘤生长、减轻肿瘤相关疼痛、减轻癌症相关病理状况、减轻癌症相关症状、癌症无进展、延长无疾病间隔、延长进展时间、诱导缓解、降低转移或延长患者存活。在另一些方面,向预期具有有利响应的患者施用单独的或与第二抗癌治疗组合的波齐替尼。
本文中还提供了组合物,其包含从人癌细胞分离的核酸;以及引物对,所述引物对可扩增人EGFR或HER2编码序列的外显子20的至少第一部分。在一些方面,组合物还包含经标记的探针分子,当所述序列中存在突变时,经标记的探针分子可与所述人EGFR或HER编码序列的外显子20的第一部分特异性杂交。在某些方面,组合物还包含热稳定的DNA聚合酶。在一些方面,组合物还包含dNTP。在一些方面,当存在选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771delinsFH和N771dupNPH的突变时,经标记的探针与人EGFR编码序列的外显子20的第一部分杂交。在某些方面,当存在选自A775insV G776C、A775insYVMA、G776V、G776C V777insV、G776CV777insC、G776del insVV、G776del insVC和P780insGSP的突变时,经标记的探针与人HER2编码序列的外显子20的第一部分杂交。
在另一个实施方案中,提供了分离的核酸,其编码突变体EGFR蛋白,其中所述突变体蛋白与野生型人EGFR的不同之处在于一个或更多个EGFR外显子20突变,所述突变包含第763至778位氨基酸之间3至18个核苷酸的点突变、插入和/或缺失。在一些方面,所述一个或更多个EGFR外显子20突变在选自A763、A767、S768、V769、D770、N771、P772和H773的一个或更多个残基处。在某些方面,一个或更多个外显子20突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771delinsFH和N771dupNPH。在一些特别的方面,所述核酸包含SEQ ID NO:8、9、10、11或12的序列。
在另一个实施方案中,提供了分离的核酸,其编码突变体HER2蛋白,其中所述突变体蛋白与野生型人HER2的不同之处在于一个或更多个HER2外显子20突变,所述突变包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。在一些方面,所述一个或更多个HER2外显子20突变在残基A775、G776、S779和/或P780处。在某些方面,所述一个或更多个HER2外显子20突变选自A775insVG776C、A775insYVMA、G776V、G776CV777insV、G776C V777insC、G776del insVV、G776del insVC和P780insGSP。在一些特别的方面,所述核酸包含SEQ ID NO:14、15、16、17或18的序列。
本发明的另一些目的、特征和优点将从以下详细描述中变得明显。然而,应理解,详细描述和具体实例尽管指出了本发明的一些优选实施方案,但是仅作为举例说明给出,因为通过本详细描述,在本发明精神和范围之内的多种变化和修改对于本领域技术人员而言将变得明显。
附图说明
以下附图构成本说明书的一部分并且为了进一步示出本发明的某些方面而包括在内。通过参照与本文中提出的一些具体实施方案的详细描述组合的这些附图中的一个或更多个可更好地理解本发明。
图1A至1J:外显子20插入突变诱导对共价和非共价TKI的新生(denovo)抗性。(图1A)具有经典和外显子20EGFR突变的患者的无进展存活(PFS)表现出对第一线治疗的抗性。具有外显子20插入的患者的存活百分比降低。(图1B)在稳定的Ba/F3模型中产生的EGFR和HER2外显子20插入突变的示意图。用第1代、第2代和第3代TKI处理72小时的表达EGFR(图1C至1E)和(图1F至1H)HER2外显子20插入突变的Ba/F3细胞系之细胞生存力的剂量响应曲线。(图1C至1H)绘制6种细胞系对各个浓度的平均值±SEM(n=3)。(图1I)EGFR D770insNPG和T790M的3D建模。P环和α-c-螺旋移动进入到结合袋中导致空间位阻,将AZD9291推出结合袋。(图1J)HER2 A775insYVMA和WT的3D建模。P环和α-c-螺旋整体移动进入到结合袋中导致结合袋的尺寸总体减小。
图2A至2G:波齐替尼强效抑制EGFR和HER2外显子20插入突变。用波齐替尼处理72小时的表达EGFR(图2A)和HER2(图2B)外显子20插入突变的Ba/F3细胞系之细胞生存力的剂量响应曲线。绘制各个单独细胞系对各个浓度的平均值±SEM(n=3)。(图2C)Western印迹证实在波齐替尼处理2小时之后Ba/F3细胞系中的p-EGFR和p-HER2的抑制(n=2)。(图2D)Ba/F3EGFR外显子20插入位置与氨基酸位置的相关性(n=2)。使用GraphPad Prism确定皮尔逊(Pearson)相关性和p值。(图2E)用波齐替尼或阿法替尼处理72小时的患者来源的表达EGFR A767dupASV的细胞系CUTO14和(图2F)表达EGFR N771del insFH的YUL0019之细胞生存力的剂量响应曲线(n=3)。(图2F)在用阿法替尼、奥希替尼、罗西替尼或波齐替尼孵育72小时之后,相对于Ba/F3EGFR T790M细胞系之IC50值归一化的EGFR突变体Ba/F3细胞之IC50值(n=3)。(图2G)条代表平均值±SEM。大于1的值指示与T790M相比更低效的抑制,而小于1的值指示与T790M相比外显子20插入的更强效的抑制。
图3A至3H:在EGFR和HER2外显子20插入突变小鼠模型中,波齐替尼减小肿瘤负荷。每天用载剂(EGFR n=5并且HER2n=4)、20mg/kg阿法替尼(EGFR n=4)或10mg/kg波齐替尼(EGFR n=5并且HER2n=6)处理EGFR D770insNPG(图3A)或HER2A775insYVMA(图3B)小鼠持续4周。通过MRI测量的肿瘤体积变化的瀑布图(Waterfall plot)示出了在EGFR和HER2GEMM中4周时波齐替尼分别实现85%和60%的肿瘤抑制。(图3A至3B)使用双侧t检验来计算p值。在波齐替尼处理之前和处理4周之后,EGFR(图3C)和HER2(图3D)GEMM的代表性MRI图像示出了稳健的肿瘤消退。用10mg/kg的波齐替尼5天/周处理EGFR D770insNPG(图3E)(n=4)和HER2A775insYVMA(图3F)(n=6)12周的肿瘤体积图显示出小鼠持续响应于波齐替尼治疗。(图3G)用阿法替尼或波齐替尼处理的YUL-0019(EGFR N771delinsFH)细胞。用10mg/kg波齐替尼处理的细胞具有最小的肿瘤体积,并且用5mg/kg处理的具有第2最小的肿瘤体积。(图3H)用载剂对照(n=6)、5mg/kg(n=6)或10mg/kg(n=3)的波齐替尼处理EGFR H773insNPHPDX小鼠。用波齐替尼处理的小鼠肿瘤体积减小。瀑布图表明在所有波齐替尼处理的小鼠中肿瘤负荷降低>85%,并且在9只波齐替尼处理的小鼠中的8只中,异种移植物完全减小至残留圆块(residual bolus)。单因素ANOVA分析与Tukey's检验组合使用以确定统计学显著性,***,p<0.0001。
图4A至4C:EGFR和HiER2外显子20插入突变是激活突变(activating mutation)。(图4A)具有EGFR外显子20插入的个体患者的瀑布图示出了对厄洛替尼、吉非替尼或阿法替尼的新生抗性。患者突变列在各个表示条下方。(图4B)表达EGFR外显子20插入突变的稳定Ba/F3细胞系在IL-3非依赖性条件下是活的,与表达Ba/F3空载体的细胞或表达EGFRWT的Ba/F3细胞不同,表明EGFR外显子20插入是激活突变。(图4C)表达不同HER2突变的11种稳定的Ba/F3细胞系的IL-3非依赖性生长表明大多数HER2激活突变在HER2的外显子20内。除L755P之外,所有激活突变均为HER2外显子20插入突变。(图4B至C)通过Cell TiterGlo测定法确定细胞生存力。绘制各个细胞系的平均值±SEM(n=3)。
图5:用第1代、第2代和第3代TKI处理72小时的表达EGFR外显子20插入突变的单独Ba/F3细胞系之细胞生存力的剂量响应曲线。绘制各个浓度的平均值±SEM(n=3)。
图6:用第1代、第2代和第3代TKI处理72小时的表达HER2外显子20插入突变的单独Ba/F3细胞系之细胞生存力的剂量响应曲线。绘制各个浓度的平均值±SEM(n=3)。
图7A至7D:在残基A763之后的EGFR和HER2外显子20插入突变对第1代和第3代TKI具有抗性。将具有EGFR外显子20插入的Ba/F3细胞血清饥饿1小时,然后用指定剂量的(图7A)厄洛替尼或(图7C)奥希替尼处理2小时(N=2)。使用Photoshop量化(图7B)厄洛替尼处理和(图7D)奥希替尼处理之后的p-EGFR和p-HER2水平。在Graphpad Prism中将值绘图,并且条代表平均值±SEM。(N=2)p<0.05(*),p<0.01(**)或p<0.001(***)。
图8A至8E:EGFR和HER2外显子20插入突变在体外对波齐替尼敏感。(图8A)使用Photoshop量化在指定的Ba/F3细胞系中波齐替尼处理2小时之后p-EGFR和p-HER2的Western印迹。在Graphpad Prism中将值绘图,并且条代表平均值±SEM。(N=2)(图8B)在指定剂量的阿法替尼或波齐替尼3小时之后CUTO-14患者来源的细胞系的Western印迹(N=3)。(图8C)在CUTO-14细胞系中指定剂量的阿法替尼或波齐替尼的3小时之后,来自Western印迹的p-EGFR的定量。波齐替尼处理导致p-EGFR降低。(图8D)IC50值相对于Ba/F3细胞系的相对表达的线性回归图示出了表达与对波齐替尼的敏感性之间没有相关性(n=2)。(图8E)IC50值相对于HER2受体内的突变位置的线性回归图示出了在HER2突变体Ba/F3细胞系中,位置与对波齐替尼的敏感性之间没有相关性(n=2)。使用Graphpad prism计算皮尔逊相关性和p值。p<0.05(*),p<0.01(**)或p<0.001(***)。
图9:C797S和EMT是体外波齐替尼抗性的两种不同机制。用波齐替尼处理72小时的EGFR突变体Ba/F3细胞系之细胞生存力的剂量响应曲线。绘制各个浓度的平均值±SEM(n=3)。
图10:用指定的TKI处理的MCF10A HER2G776del insVC细胞系之细胞生存力的剂量响应曲线。
具体实施方式
尽管表皮生长因子受体(epidermal growth factor receptor,EGFR)突变体非小细胞肺癌(non-small cell lung cancer,NSCLC)的大多数激活突变对可用的EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)敏感,但在EGFR和HER2的外显子20中具有的改变的子集本质上是具有抗性的。本研究利用电脑模拟(in silico)、体外和体内测试来模拟由这些外显子20突变诱导的结构的改变并鉴定有效的抑制剂。3D建模揭示了限制使大的刚性抑制剂结合的药物结合袋的尺寸的显著改变。发现由于波齐替尼的小的尺寸和柔性,其能够规避这些空间变化,并且其是EGFR或HER2外显子20突变体蛋白的强效且具有相对选择性的抑制剂。波齐替尼在突变体外显子20 EGFR或HER2 NSCLC患者来源的异种移植物(PDX)模型和基因工程小鼠模型中也具有强效活性。因此,这些数据确定波齐替尼为EGFR/HER2外显子20突变之强效的临床活性抑制剂,并举例说明了可规避由这些插入诱导的空间变化之激酶抑制剂的分子特征。
因此,本公开内容的某些实施方案提供了用于治疗具有EGFR和/或HER2外显子20突变(例如外显子20插入)的癌症患者的方法。特别地,本发明方法包括向被确定具有EGFR和/或HER外显子20插入突变的患者施用波齐替尼(也称为HM781-36B)或阿法替尼。波齐替尼的尺寸和柔性克服了空间位阻,在低的纳摩尔浓度下抑制EGFR和HER2外显子20突变体。因此,波齐替尼或阿法替尼以及结构类似的抑制剂是强效的EGFR或HER2抑制剂,其可用于靶向对不可逆的第2代和第3代TKI具有抗性的EFGR和HER2外显子20插入二者。
I.定义
如本文中在说明书中所用的,没有数量词修饰的名词可意指一个/种或更多个/种。如本文中在权利要求书中所用的,当与词语“包含/包括”联合使用时,没有数量词修饰的名词可意指一个/种或多于一个/种。
虽然本公开内容支持指仅替代方案和“和/或”的定义,但是权利要求书中术语“或/或者”的使用用于意指“和/或”,除非明确地指出仅指替代方案或者替代方案相互排斥。本文中使用的“另一”可意指至少第二个或更多个。
在本申请通篇,术语“约/大约”用于表示值包括用于确定所述值的装置、方法之误差的固有变化或所研究对象之间存在的变化。
“治疗”包括:(1)在经历或显示出疾病之病理状况或症状的对象或患者中抑制疾病(例如,阻止病理状况和/或症状的进一步发展),(2)在经历或显示出疾病之病理状况或症状的对象或患者中改善疾病(例如,逆转病理状况和/或症状),和/或(3)在经历或显示出疾病之病理状况或症状的对象或患者中实现疾病的任何可测量的减轻。例如,治疗可包括施用有效量的波齐替尼或阿法替尼。
“预防”包括:(1)在可处于疾病风险之中和/或易患疾病但尚未经历或显示出疾病的任何或所有病理状况或症状的对象或患者中抑制疾病的发生,和/或(2)在可处于疾病风险之中和/或易患疾病但尚未经历或显示出疾病的任何或全部病理状况或症状的对象或患者中减慢疾病之病理状况或症状的发生。
本文中使用的术语“患者”或“对象”是指活的哺乳动物生物体,例如人、猴、牛、绵羊、山羊、狗、猫、小鼠、大鼠、豚鼠或其转基因物种。在某些实施方案中,患者或对象是灵长类动物。人患者的一些非限制性实例是成年人、青少年、婴儿和胎儿。
术语“有效”如该术语在说明书和/或权利要求书中使用的,意指足以实现期望的、预期的或想要的结果。当在用化合物治疗患者或对象的情况下使用时,“有效量”、“治疗有效量”或“药学有效量”意指当向对象或患者施用以治疗或预防疾病时化合物的量是足以实现疾病的此类治疗或预防的量。
本文中使用的术语“IC50”是指为所获得的最大响应之50%的抑制剂量。这种定量量度表明抑制给定的生物、生化或化学过程(或过程的组分,即酶、细胞、细胞受体或微生物)的一半需要多少特定药物或其他物质(抑制剂)。
“抗癌”剂能够负面地影响对象中的癌细胞/肿瘤,例如通过促进癌细胞的杀伤、诱导癌细胞的凋亡、降低癌细胞的生长速率、降低转移的发生率或数量、减小肿瘤尺寸、抑制肿瘤生长、降低向肿瘤或癌细胞的血液供应、促进针对癌细胞或肿瘤的免疫应答、预防或抑制癌症的进展或者提高患有癌症的对象的寿命。
术语“插入”或“插入突变”是指向DNA序列中添加一个或更多个核苷酸碱基对。例如,EGFR外显子20插入突变可发生在第767至774位氨基酸之间的约2至21个碱基对。在另一个实例中,HER2外显子20插入突变包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个插入。示例性EGFR和HER外显子20插入突变描绘于本公开内容的图1中。
“杂交”是指核酸之间的结合。杂交的条件可根据待结合的核酸的序列同源性而变化。因此,如果对象核酸之间的序列同源性高,则使用严格条件。如果序列同源性低,则使用温和条件。当杂交的条件严格时,杂交特异性提高,并且杂交特异性的这种提高导致非特异性杂交产物的产率降低。然而,在温和的杂交条件下,杂交特异性降低,并且杂交特异性的这种降低导致非特异性杂交产物的产率提高。
“探针”是指长度为至少8个核苷酸并且由于探针中的至少一个序列与靶区域中的序列的互补性而与靶序列形成杂合结构的多核苷酸。多核苷酸可由DNA和/或RNA构成。在某些实施方案中,探针是经可检测标记的。探针的尺寸可显著变化。通常来说,探针的长度为例如至少8至15个核苷酸。另一些探针为例如至少20、30或40个核苷酸长。另一些探针稍微更长,为至少例如50、60、70、80或90个核苷酸长。探针也可以是落入上述范围内的任何具体长度。优选地,探针不包含与在聚合酶链式反应期间用于引发靶序列的序列互补的序列。
“寡核苷酸”或“多核苷酸”是指单链或双链脱氧核糖核苷酸或核糖核苷酸的聚合物,其可以是未经修饰的RNA或DNA或者经修饰的RNA或DNA。
“经修饰的核糖核苷酸”或脱氧核糖核苷酸是指可用于替代核酸中天然存在的碱基的分子,并且包括但不限于经修饰的嘌呤和嘧啶,稀有碱基(minor base),可转化的核苷,嘌呤和嘧啶的结构类似物,经标记、衍生化和修饰的核苷和核苷酸,缀合的核苷和核苷酸,序列修饰物,末端修饰物,间隔子修饰物,以及具有骨架修饰的核苷酸,包括但不限于核糖经修饰的核苷酸,氨基磷酸酯,硫代磷酸酯,氨基膦酸酯,甲基膦酸酯,甲基氨基磷酸酯,甲基氨基膦酸酯,5’-β-氰乙基氨基磷酸酯,亚甲基膦酸酯,二硫代磷酸酯,肽核酸,非手性和中性核苷酸间连接。
“变体”是指分别通过一个或更多个核苷酸或氨基酸的交换、缺失或插入而相对于野生型或个体的群体中最常见的形式不同的多核苷酸或多肽。交换、缺失或插入的核苷酸或氨基酸的数量可以是1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更多个,例如25、30、35、40、45或50个。
“引物”或“引物序列”是指与靶核酸序列(例如,待扩增的DNA模板)杂交以引发核酸合成反应的寡核苷酸。引物可以是DNA寡核苷酸、RNA寡核苷酸或嵌合序列。引物可包含天然、合成或经修饰的核苷酸。引物长度的上限和下限均根据经验来确定。引物长度的下限是在核酸扩增反应条件下与靶核酸杂交之后形成稳定的双链体所需的最小长度。非常短的引物(通常小于3至4个核苷酸长)在这样的杂交条件下不与靶核酸形成热力学稳定的双链体。上限通常由靶核酸中除预定核酸序列之外的区域中形成双链体的可能性来确定。通常来说,合适的引物长度为约10至约40个核苷酸长。在某些实施方案中,例如,引物可以是10至40、15至30或10至20个核苷酸长。当置于适当的条件下时,引物能够充当多核苷酸序列上的合成引发点。
“检测”、“可检测的”及其语法等同物是指确定靶核酸序列之存在和/或数量和/或特性的方式。在一些实施方案中,检测发生扩增靶核酸序列。在另一些实施方案中,靶核酸的测序可表征为“检测”靶核酸。连接至探针的标记可包括可通过例如化学或物理的方式检测的本领域中已知的多种不同标记中的任一种。可连接至探针的标记可包括例如荧光和发光材料。
“扩增”及其语法等同物是指以模板依赖性的方式(包括但不限于用于扩增核酸序列的广泛范围的技术)线性地或指数性地复制靶核酸序列的至少一部分的任何方法。用于进行扩增步骤的一些示例性方法包括:连接酶链式反应(ligase chain reaction,LCR)、连接酶检测反应(ligase detection reaction,LDR)、连接之后Q-复制酶扩增、PCR、引物延伸、链置换扩增(strand displacement amplification,SDA)、超支化链置换扩增、多置换扩增(multiple displacement amplification,MDA)、基于核酸链的扩增(nucleic acidstrand-based amplification,NASBA)、两步多重扩增、滚环扩增(rolling circleamplification,RCA)、重组酶-聚合酶扩增(recombinase-polymerase amplification,RPA)(TwistDx,Cambridg,UK)和自持续序列复制(self-sustained sequencereplication,3SR),包括多版本或其组合,例如但不限于OLA/PCR、PCR/OLA、LDR/PCR、PCR/PCR/LDR、PCR/LDR、LCR/PCR、PCR/LCR(也称为组合链式反应-CCR)等。此类技术的描述尤其可见于Sambrook et al.Molecular Cloning,第三版中。
“EGFR”或“表皮生长因子受体”或“EGFR”是指酪氨酸激酶细胞表面受体,并且由作为GenBank登录号NM_005228.3、NM_201282.1、NM_201283.1和NM_201284.1出现的四种替代转录物之一编码。EGFR的变体包括外显子20中的插入。
“HER2”或“ERBB2”是EGFR/ErbB家族的成员,并且作为GenBank登录号NM_004448.2出现。HER2的变体包括外显子20中的插入。
本文中通常使用的“可药用”是指与合理的效益/风险比相称的在合理的医学判断范围内适用于与人和动物的组织、器官和/或体液接触而无过度的毒性、刺激性、变应性应答或者其他问题或并发症的那些化合物、材料、组合物和/或剂型。
“可药用盐”意指本发明化合物的盐,其是如上文定义的可药用的并且其具有期望的药理学活性。这样的盐的一些非限制性实例包括与无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸和磷酸;或与有机酸形成的酸加成盐,所述有机酸例如1,2-乙二磺酸、2-羟基乙磺酸、2-萘磺酸、3-苯基丙酸、4,4’-亚甲基双(3-羟基-2-烯-1-羧酸)、4-甲基双环[2.2.2]辛-2-烯-1-羧酸、乙酸、脂肪族单羧酸和二羧酸、脂肪族硫酸、芳香族硫酸、苯磺酸、苯甲酸、樟脑磺酸、碳酸、肉桂酸、柠檬酸、环戊烷丙酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、庚酸、己酸、羟基萘甲酸、乳酸、月桂基硫酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏康酸、o-(4-羟基苯甲酰基)苯甲酸、草酸、对氯苯磺酸、苯基取代的烷酸、丙酸、对甲苯磺酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、酒石酸、叔丁基乙酸和三甲基乙酸。可药用盐还包括当存在的酸性质子能够与无机碱或有机碱反应时可形成的碱加成盐。可接受的无机碱包括氢氧化钠、碳酸钠、氢氧化钾、氢氧化铝和氢氧化钙。可接受的有机碱的一些非限制性实例包括乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇和N-甲基葡糖胺。应认识到,形成本发明的任何盐的一部分的特定阴离子或阳离子不是关键的,只要该盐作为整体在药理学上是可接受的即可。可药用盐及其制备和使用方法的另外的实例示于Handbookof Pharmaceutical Salts:Properties,and Use(P.H.Stahl&C.G.Wermuth编辑,VerlagHelvetica Chimica Acta,2002)。
II.EGFR和HER2外显子20突变
本公开内容的某些实施方案涉及确定对象是否具有一个或更多个EGFR和/或HER2外显子20突变,例如插入突变,特别是一个或更多个如图1中所示的插入突变。对象可具有2、3、4或更多个EGFR外显子20突变和/或HER2外显子20突变。突变检测方法是本领域中已知的,包括PCR分析和核酸测序以及FISH和CGH。在一些特别的方面,通过DNA测序(例如来自于肿瘤或来自血浆的循环游离DNA)来检测外显子20突变。
EGFR外显子20突变可包含第763至778位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。所述一个或更多个EGFR外显子20突变可位于选自A763、A767、S768、V769、D770、N771、P772和H773的一个或更多个残基处。
EGFR外显子20插入可包括H773_V774insH、A767_v769ASV、N771_P772insH、D770_N771insG、H779_V774insH、N771delinsHH、S768_D770dupDVD、A767_V769dupASV、A767_V769dupASV、P772_H773dup、N771_H773dupNPH、S768_D770dupSVD、N771delinsGY、S768_D770delinsSVD、D770_D770delinsGY、A767_V769dupASV和/或H773dup。在一些特别的方面,外显子20突变是A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、H773insNPH、N771del insGY、N771del insFH和/或N771dupNPH。
在一些方面,对象可具有或发生在EGFR残基C797处的突变,其可导致对TKI(例如波齐替尼)的抗性。因此,在某些方面,对象被确定不具有在EGFR C797处的突变。
HER2外显子20突变可包含第770至785位氨基酸之间3至18个核苷酸的一个或更多个点突变、插入和/或缺失。所述一个或更多个HER2外显子20突变可在残基A775、G776、S779和/或P780处。所述一个或更多个HER2外显子20突变可以是A775insV G776C、A775insYVMA、G776V、G776C V777insV、G776C V777insC、G776del insVV、G776del insVC和/或P780insGSP。
患者样品可以是任何身体组织或流体,其包含来自对象中肺癌的核酸。在某些实施方案中,样品将是包含循环肿瘤细胞或无细胞DNA的血液样品。在另一些实施方案中,样品可以是组织,例如肺组织。肺组织可来自肿瘤组织,并且可以是新鲜冷冻的或经福尔马林固定、经石蜡包埋的(formalin-fixed,paraffin-embedded,FFPE)。在某些实施方案中,获得肺肿瘤FFPE样品。
适用于本文中所述方法的样品包含遗传物质,例如基因组DNA(genomic DNA,gDNA)。一般来说,基因组DNA从生物样品(例如血液或口腔被覆的黏膜刮屑)中提取,但也可从其他生物样品(包括尿、肿瘤或祛痰物(expectorant))中提取。一般来说,样品本身将包含有核细胞(例如,血液或颊细胞)或从对象移除的组织,包括正常组织或肿瘤组织。用于获得、处理和分析样品的方法和试剂是本领域中已知的。在一些实施方案中,在健康护理提供者的帮助下(例如抽血)获得样品。在一些实施方案中,在没有健康护理提供者的帮助下获得样品,例如,其中样品是非侵入性获得的,例如使用颊拭子或刷获得的包含颊细胞的样品或漱口水样品。
在一些情况下,可处理生物样品用于DNA分离。例如,细胞或组织样品中的DNA可与样品的其他组分分离。可使用本领域中已知的标准技术从生物样品中收获细胞。例如,可通过离心细胞样品并重悬沉淀的细胞来收获细胞。细胞可重悬于缓冲溶液(例如磷酸缓冲盐水(phosphate-buffered saline,PBS))中。在离心细胞混悬液以获得细胞沉淀之后,可裂解细胞以提取DNA,例如gDNA。参见,例如,Ausubel et al.(2003)。可浓缩和/或纯化样品以分离DNA。获自对象的所有样品(包括经受任何类别的进一步处理的那些)被认为是从对象获得的。常规方法可用于从生物样品提取基因组DNA,包括例如酚提取(phenolextraction)。或者,基因组DNA可用试剂盒(例如组织试剂盒(Qiagen,Chatsworth,Calif.)和/>基因组DNA纯化试剂盒(Promega))进行提取。样品之来源的一些非限制性实例包括尿、血液和组织。
可使用本领域中已知的方法来确定本文中所述的EGFR或HER2外显子20突变(例如外显子20插入突变)的存在或不存在。例如,凝胶电泳、毛细管电泳、尺寸排阻色谱法、测序和/或阵列可用于检测插入突变的存在或不存在。在期望的情况下,可使用本领域中已知的方法(例如PCR)来完成核酸的扩增。在一个实例中,样品(例如,包含基因组DNA的样品)获自对象。然后检查样品中的DNA以确定本文中所述的插入突变的特性。插入突变可通过本文中所述的任何方法来检测,例如通过测序或通过基因组DNA、RNA或cDNA中的基因与核酸探针(例如DNA探针(其包括eDNA和寡核苷酸探针)或RNA探针)的杂交来检测。核酸探针可设计成与特定变体特异性或优先杂交。
一般来说,一组探针是指一组引物(通常是引物对)和/或经可检测标记的探针,其用于检测用于本公开内容的可行治疗建议的靶遗传变异(例如,EGFR和/或HER2外显子20突变)。引物对用于扩增反应以限定扩增子,所述扩增子跨越针对各个前述基因的靶遗传变异的区域。通过一组相匹配的探针检测该组扩增子。在一个示例性实施方案中,本发明方法可使用TaqManTM(Roche Molecular Systems,Pleasanton,Calif.)测定法,其用于检测一组靶遗传变异,例如EGFR和/或HER2外显子20突变。在一个实施方案中,该组探针是用于产生通过核酸测序反应(例如下一代测序反应)检测的扩增子的一组引物。在这些实施方案中,例如,可使用AmpliSEQTM(Life Technologies/Ion Torrent,Carlsbad,Calif.)或TruSEQTM(Illumina,San Diego,Calif.)技术。
可使用本领域中已知的技术(包括但不限于序列分析和电泳分析)进行核酸标志物的分析。序列分析的一些非限制性实例包括Maxam-Gilbert测序、Sanger测序、毛细管阵列DNA测序、热循环测序(Sears et al.,1992)、固相测序(Zimmerman et al.,1992)、使用质谱(例如基质辅助激光解吸/电离飞行时间质谱(MALDI-TOF/MS))的测序(Fu et al.,1998)以及通过杂交的测序(Chee et al.,1996;Drmanac et al.,1993;Drmanac et al.,1998)。电泳分析的一些非限制性实例包括平板凝胶电泳(例如琼脂糖或聚丙烯酰胺凝胶电泳)、毛细管电泳和变性梯度凝胶电泳。另外,可使用可从公司商购的试剂盒和仪器(例如Life Technologies/Ion Torrent PGM或Proton、Illumina HiSEQ或MiSEQ、以及Roche/454下一代测序系统)进行下一代测序方法。
核酸分析的其他方法可包括直接人工测序(Church and Gilbert,1988;Sangeret al.,1977;美国专利No.5,288,644);自动荧光测序;单链构象多态性分析(single-stranded conformation polymorphism assay,SSCP)(Schafer et al.,1995);钳位变性凝胶电泳(clamped denaturing gel electrophoresis,CDGE);二维凝胶电泳(two-dimensional gel electrophoresis,2DGE或TDGE);构象敏感性凝胶电泳(conformationalsensitive gel electrophoresis,CSGE);变性梯度凝胶电泳(denaturing gradient gelelectrophoresis,DGGE)(Sheffield et al.,1989);变性高效液相色谱(denaturing highperformance liquid chromatography)(DHPLC,Underhill et al.,1997);红外基质辅助激光解吸/电离(infrared matrix-assisted laser desorption/ionization,IR-MALDI)质谱(WO 99/57318);迁移率变动分析(Orita et al.,1989);限制性酶分析(Flavell etal.,1978;Geever et al.,1981);定量实时PCR(Raca et al.,2004);异源双链体分析(heteroduplex analysis);化学错配切割(chemical mismatch cleavage,CMC)(Cottonet al.,1985);核糖核酸酶保护测定法(RNase protection assay)(Myers et al.,1985);使用识别核苷酸错配的多肽,例如大肠杆菌(E.coli)mutS蛋白;等位基因特异性PCR,以及这样的方法的组合。参见例如美国专利公开No.2004/0014095,其通过引用整体并入本文。
在一个实例中,鉴定样品中EGFR和/或HER2突变的方法包括使来自所述样品的核酸与核酸探针接触,所述核酸探针能够与编码突变的EGFR或HER2蛋白之核酸或其并入了突变的片段特异性杂交;并检测所述杂交。在一个具体实施方案中,所述探针例如用放射性同位素(3H、32P或33P)、荧光剂(罗丹明(rhodamine)或荧光索)或显色剂(chromogenic agent)可检测地标记。在一个特别的实施方案中,探针是反义寡聚体,例如PNA、吗啉代-氨基磷酸酯、LNA或2’-烷氧基烷氧基。探针可以是约8个核苷酸至约100个核苷酸、或约10至约75个、或约15至约50个、或约20至约30个。在另一方面,本公开内容的所述探针在用于鉴定样品中EGFR或HER2突变的试剂盒中提供,所述试剂盒包含特异性杂交至EGFR或HER2基因中的突变位点或与其相邻的寡核苷酸。所述试剂盒还可包含用于基于使用所述试剂盒的杂交测试结果,用波齐替尼或阿法替尼治疗患有包含EGFR或HER2插入突变之肿瘤的患者的说明书。
在另一个方面,用于检测样品中外显子20突变的方法包括扩增来自所述样品的对应于所述EGFR基因或HER2的外显子20的核酸、或其疑似包含突变之片段,并比较经扩增的核酸的电泳迁移率与相应的野生型EGFR或HER2基因或其片段的电泳迁移率。迁移率的差异表明经扩增的核酸序列中存在突变。可在聚丙烯酰胺凝胶上确定电泳迁移率。
或者,可使用酶促突变检测(Enzymatic Mutation Detection,EMD)分析核酸以检测突变(Del Tito et al.,1998)。EMD使用噬菌体解离酶T4内切核酸酶VII,其沿双链DNA扫描直至其检测到并切割由点突变、插入和缺失导致的碱基对错配引起的结构扭曲。检测到由解离酶切割形成的两个短片段(例如通过凝胶电泳)表明存在突变。EMD方法的优点是直接从PCR反应鉴定所测定的点突变、缺失和插入的单一方案,消除了对样品纯化的需要,缩短了杂交时间,并提高了信噪比。可测定包含高至20倍过量的正常DNA和尺寸大至4kb的片段的混合样品。然而,EMD扫描不识别在突变阳性样品中发生的特定碱基变化,如果必需的话,需要另外的测序操作来鉴定突变。如在美国专利No.5,869,245中所示出的,可类似于解离酶T4内切核酸酶VII使用CEL I酶。
III.治疗方法
本文中还提供了用于在个体中治疗或延迟癌症进展的方法,其包括对于被确定具有EGFR和/或HER2外显子突变(例如外显子20插入)的对象,向个体施用有效量的波齐替尼、阿法替尼或结构类似的抑制剂。对象可具有多于一个EGFR和/或HER外显子20突变。
考虑用于进行治疗的癌症的一些实例包括肺癌、头颈癌、乳腺癌、胰腺癌、前列腺癌、肾癌、骨癌、睾丸癌、宫颈癌、胃肠癌、淋巴瘤、肺中的肿瘤前病变、结肠癌、黑素瘤和膀胱癌。在一些特别的方面,癌症是非小细胞肺癌。
在一些实施方案中,对象是哺乳动物,例如灵长类,优选高级灵长类,例如人(例如,患有本文中所述病症或处于其患病风险之中的患者)。在一个实施方案中,对象需要增强免疫应答。在某些实施方案中,对象是免疫受损的或处于免疫受损的风险之中。例如,对象正在经历或已经历化学治疗性治疗和/或放射治疗。或者,或组合地,对象是由于感染而免疫受损的或处于由于感染而免疫受损的风险之中。
某些实施方案涉及向被确定具有EGFR或HER2外显子20突变(例如外显子20插入)的对象施用波齐替尼(也称为HM781-36B、HM781-36、以及1-[4-[4-(3,4-二氯-2-氟苯胺基)-7-甲氧基喹唑啉-6-基]氧基哌啶-1-基]丙-2-烯-1-酮)。波齐替尼是基于喹唑啉的泛HER(pan-HER)抑制剂,其不可逆地阻断通过酪氨酸激酶受体的HER家族(包括HER1、HER2和HER4)的信号传导。波齐替尼或结构类似的化合物(例如,美国专利No.8,188,102和美国专利公开No.20130071452;通过引用并入本文)可用于本发明方法。
B.药物组合物
本文中还提供了包含波齐替尼或阿法替尼和可药用载体的药物组合物和制剂,其用于被确定具有EGFR或HER2外显子20(例如外显子20插入)的对象。
本文中所述的药物组合物和制剂可以以经冻干的制剂或水溶液的形式,通过将具有期望纯度程度的活性成分(例如抗体或多肽)与一种或更多种任选的可药用载体混合来制备(Remington's Pharmaceutical Sciences第22版,2012)。可药用载体在所使用的剂量和浓度下通常对接受者无毒,并且包括但不限于:缓冲剂,例如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如十八烷基二甲基苄基氯化铵;氯化六甲铵;苯扎氯铵;苄索氯铵;酚、丁醇或苄醇;对羟基苯甲酸烷基酯,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;以及间甲酚);低分子量(少于约10个残基)多肽;蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,例如聚乙烯吡咯烷酮;氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,例如EDTA;糖,例如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成盐反荷离子,例如钠;金属配合物(例如Zn-蛋白质配合物);和/或非离子表面活性剂,例如聚乙二醇(PEG)。本文中的示例性可药用载体还包括形成空隙的(insterstitial)药物分散剂,例如可溶性中性活性透明质酸酶糖蛋白(sHASEGP),例如人可溶性PH-20透明质酸酶糖蛋白,例如rHuPH20(Baxter International,Inc.)。某些示例性sHASEGP(包括rHuPH20)和使用的方法描述于美国专利公开No.2005/0260186和2006/0104968中。在一个方面,sHASEGP与一种或更多种另外的糖胺聚糖酶(例如软骨素酶)组合。
C.组合治疗
在某些实施方案中,一些本发明实施方案的组合物和方法涉及波齐替尼或阿法替尼与至少一种另外的治疗组合。另外的治疗可以是放射治疗、手术(例如,肿块切除术和乳房切除术)、化学治疗、基因治疗、DNA治疗、病毒治疗、RNA治疗、免疫治疗、骨髓移植、纳米治疗、单克隆抗体治疗或前述的组合。另外的治疗可以是辅助或新辅助治疗的形式。
在一些实施方案中,另外的治疗是施用小分子酶抑制剂或抗转移剂。在一些实施方案中,另外的治疗是施用副作用限制剂(例如,旨在降低治疗副作用的发生和/或严重程度的药剂,例如抗恶心剂等)。在一些实施方案中,另外的治疗是放射治疗。在一些实施方案中,另外的治疗是手术。在一些实施方案中,另外的治疗是放射治疗和手术的组合。在一些实施方案中,另外的治疗是γ辐照。在一些实施方案中,另外的治疗是靶向PBK/AKT/mTOR途径的治疗、HSP90抑制剂、微管蛋白抑制剂、凋亡抑制剂和/或化学预防剂。另外的治疗可以是本领域中已知的一种或更多种化学治疗剂。
波齐替尼或阿法替尼可在相对于另外的癌症治疗(例如免疫检查点治疗)之前、期间、之后或以多种组合施用。施用可以以同时至间隔数分钟至数天至数周进行。在其中将波齐替尼或阿法替尼与另外的治疗剂分开提供给患者的一些实施方案中,通常将确保在每次递送的时间之间相当长的一段时间内不会失效,使得两种化合物仍然能够对患者发挥有利的组合作用。在此类情况下,考虑在彼此相隔约12小时至24小时或72小时内,并且更特别地,在彼此相隔约6小时至12小时内,可为患者提供抗体治疗和抗癌治疗。在一些情况下,可期望显著地延长治疗的时间周期,其中各施用之间间隔数天(2、3、4、5、6或7)至数周(1、2、3、4、5、6、7或8)。
可使用多种组合。对于以下的实例,波齐替尼或阿法替尼是“A”,并且抗癌治疗是“B”:
考虑到药剂的毒性(如果有的话),向患者施用本发明实施方案的任何化合物或治疗将遵循用于施用此类化合物的一般方案。因此,在一些实施方案中,存在可归因于组合治疗的监测毒性的步骤。
1.化学治疗
可根据本发明实施方案使用广泛多种的化学治疗剂。术语“化学治疗”是指使用药物来治疗癌症。“化学治疗剂”用于意指在癌症治疗中施用的化合物或组合物。这些药剂或药物通过其在细胞内的活性模式(例如其是否影响细胞周期和在什么阶段影响细胞周期)进行分类。或者,可基于药剂直接交联DNA、嵌入到DNA中或通过影响核酸合成来诱导染色体和有丝分裂畸变的能力来表征药剂。
化学治疗剂的一些实例包括:烷化剂,例如噻替派和环磷酰胺;烷基磺酸酯类,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱类(camptothecin)(包括合成类似物拓扑替康(topotecan));苔藓抑素(bryostatin);卡利抑素(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素类(cryptophycin)(特别是隐藻素1和隐藻素8);海兔毒素(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥类(nitrogen mustard),例如氯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxidehydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)和尿嘧啶氮芥(uracil mustard);硝基脲类(nitrosurea),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素类,例如烯二炔类(enediyne)抗生素(例如,加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1;达内霉素(dynemicin),包括达内霉素A;双膦酸盐类(bisphosphonate),例如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新抑癌菌素(neocarzinostatin)生色团和相关色蛋白烯二炔类抗生素生色团、阿克拉霉素(aclacinomysin)、放线菌素、氨茴霉素(authrarnycin)、氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、卡柔比星(carabicin)、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(dactinomycin)、柔红霉素、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(例如丝裂霉素C)、霉酚酸(mycophenolic acid)、诺加霉素(nogalarnycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfimromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星、链黑菌素、链脲霉素(streptozocin)、杀结核菌素、乌苯美司、净司他丁和佐柔比星;抗代谢物类,例如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、蝶罗呤(pteropterin)和三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨、6-巯基嘌呤、硫咪嘌呤(thiamiprine)和硫鸟嘌呤;嘧啶类似物,例如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、多西氟尿啶(doxifluridine)、依诺他滨和氟尿苷;雄激素类,例如卡鲁睾酮、丙酸屈他雄酮(dromostanolonepropionate)、表硫雄醇(epitiostanol)、美雄烷和睾内酯;抗肾上腺类,例如米托坦(mitotane)和曲洛司坦;叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基酮戊酸;恩尿嘧啶;氨苯吖啶(amsacrine);贝他布昔(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛;地吖醌(diaziquone);依氟鸟氨酸(elformithine);醋酸羟吡咔唑(elliptiniumacetate)埃博霉素类(epothilone);依托格鲁(etoglucid)硝酸镓;羟基脲;香菇多糖(lentinan);氯尼达明(lonidainine);美登素生物碱类(maytansinoid),例如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他丁;苯来美特(phenamet);吡柔比星;洛索蒽醌;鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼;PSK多糖复合物);雷佐生(razoxane);根毒素(rhizoxin);西索菲兰(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺;单端孢霉烯类(trichothecene)(尤其是T-2毒素、疣孢菌素A(verracurinA)、杆孢菌素A和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛;达卡巴嗪;甘露氮芥(mannomustine);二溴甘露醇;二溴卫矛醇;哌泊溴烷(pipobroman);加西托星(gacytosine);阿糖胞苷(“Ara-C”);环磷酰胺;紫杉烷类,例如紫杉醇和多西他赛(docetaxel);吉西他滨;6-硫鸟嘌呤;巯基嘌呤;铂配位复合物,例如顺铂、奥沙利铂和卡铂;长春碱;铂类;依托泊苷(VP-16);异磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺安托(novantrone);替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇,例如视黄酸;卡培他滨;卡铂、丙卡巴肼、普卡霉素(plicomycin)、吉西他滨、诺维本、法呢基蛋白转移酶抑制剂、反铂;以及以上任一种的可药用盐、酸或衍生物。
2.放射治疗
导致DNA损伤并已广泛使用的其他因素包括通常被称为γ射线、X射线的那些和/或向肿瘤细胞定向递送放射性同位素。还考虑了其他形式的DNA损伤因素,例如微波、质子束辐照(美国专利5,760,395和4,870,287)和UV辐照。最有可能所有这些因素对DNA、DNA前体、DNA的复制和修复以及染色体的组装和维持引起广泛的损害。X射线的剂量范围以50至200伦琴日剂量持续一段长时间(3至4周)至2000至6000伦琴的单次剂量。放射性同位素的剂量范围变化很大,并且取决于同位素的半衰期、所发射辐射的强度和类型、以及肿瘤细胞的摄取。
3.免疫治疗
技术人员将理解,另外的免疫治疗可与一些实施方案的方法组合或结合使用。在癌症治疗的情况下,免疫治疗剂通常依赖于使用免疫效应细胞和分子以靶向并破坏癌细胞。利妥昔单抗就是这样的一个实例。免疫效应物可以是例如对肿瘤细胞表面上的一些标志物特异的抗体。抗体单独可充当治疗的效应物,或者其可募集其他细胞以实际影响细胞杀伤。抗体还可与药物或毒素(化学治疗剂、放射性核素、蓖麻毒素A链、霍乱毒素、百日咳毒素等)缀合并且充当靶向剂。或者,效应物可以是直接或间接地与肿瘤细胞靶标相互作用的携带表面分子的淋巴细胞。多种效应物细胞包括细胞毒性T细胞和NK细胞。
已经出现抗体-药物缀合物作为癌症治疗剂开发的突破性方法。癌症在世界上是首要死亡原因之一。抗体-药物缀合物(Antibody-drug conjugate,ADC)包含与杀伤细胞的药物共价连接的单克隆抗体(MAb)。该方法将Mab针对其抗原靶标的高特异性与高效细胞毒性药物组合,产生将有效载荷(药物)递送至具有丰富水平抗原的肿瘤细胞的“武装”MAb。药物的靶向递送还使其在正常组织中的暴露最小化,导致毒性降低和治疗指数提高。FDA对两种ADC药物的批准(2011年(维汀-布仑妥昔单抗(brentuximab vedotin))和2013年/>(曲妥珠单抗美坦新(trastuzumab emtansine)或T-DM1))验证了该方法。目前存在超过30种ADC药物候选者处于癌症治疗临床试验的多个阶段(Leal etal.,2014)。随着抗体工程和接头-有效载荷优化变得越来越成熟,新ADC的发现和开发越来越依赖于适合于该方法和靶向Mab产生的新靶标的鉴定和验证。ADC靶标的两个标准是在肿瘤细胞中上调/高水平的表达和稳健的内化。
在免疫治疗的一个方面,肿瘤细胞必须携带可进行靶向的一些标志物,即,不存在于大多数其他细胞上。存在许多肿瘤标志物,并且这些肿瘤标志物中的任一种可适于本发明实施方案的情况中的靶向。常见的肿瘤标志物包括CD20、癌胚抗原、酪氨酸酶(p97)、gp68、TAG-72、HMFG、唾液酸化的路易斯抗原(Sialyl Lewis Antigen)、MucA、MucB、PLAP、层黏连蛋白受体、erb B和p155。免疫治疗的一个替代方面是将抗癌作用与免疫刺激作用组合。还存在免疫刺激分子,其包括:细胞因子,例如IL-2、IL-4、IL-12、GM-CSF、γ-IFN;趋化因子,例如MIP-1、MCP-1、IL-8;以及生长因子,例如FLT3配体。
免疫治疗的一些实例包括免疫佐剂,例如,牛分枝杆菌(Mycobacterium bovis)、恶性疟原虫(Plasmodium falciparum)、二硝基氯苯和芳香族化合物(美国专利5,801,005和5,739,169;Hui and Hashimoto,1998;Christodoulides et al.,1998);细胞因子治疗,例如干扰素α、β和γ,IL-1、GM-CSF和TNF(Bukowski et al.,1998;Davidson et al.,1998;Hellstrand et al.,1998);基因治疗,例如,TNF、IL-1、IL-2和p53(Qin et al.,1998;Austin-Ward and Villaseca,1998;美国专利5,830,880和5,846,945);以及单克隆抗体,例如抗CD20、抗神经节苷脂GM2和抗p185(Hollander,2012;Hanibuchi et al.,1998;美国专利5,824,311)。考虑一种或更多种抗癌治疗可与本文中所述的抗体治疗一起使用。
在一些实施方案中,免疫治疗可以是免疫检查点抑制剂。免疫检查点调高信号(例如共刺激分子)或调低信号。可通过免疫检查点阻断被靶向的抑制性免疫检查点包括:腺苷A2A受体(A2A receptor,A2AR)、B7-H3(也称为CD276)、B和T淋巴细胞衰减剂(B and Tlymphocyte attenuator,BTLA)、细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4,CTLA-4,也称为CD152)、吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)、杀伤细胞免疫球蛋白(killer-cellimmunoglobulin,KIR)、淋巴细胞激活基因-3(lymphocyte activation gene-3,LAG3)、程序性死亡1(programmed death 1,PD-1)、T-细胞免疫球蛋白结构域和黏蛋白结构域3(T-cell immunoglobulin domain and mucin domain 3,TIM-3)和T细胞激活的V结构域Ig抑制剂(V-domain Ig suppressor of T cell activation,VISTA)。特别地,免疫检查点抑制剂靶向PD-1轴和/或CTLA-4。
免疫检查点抑制剂可以是药物,例如小分子、重组形式的配体或受体,或者特别是抗体,例如人抗体(例如,国际专利公开WO2015016718;Pardoll,Nat Rev Cancer,12(4):252-64,2012;二者均通过引用并入本文)。可使用免疫检查点蛋白或其类似物的已知抑制剂,特别是可使用嵌合、人源化或人形式的抗体。如本领域技术人员将知晓的,替代和/或等同名称可用于本公开内容中提及的某些抗体。在本发明的上下文中,这样的替代和/或等同名称是可互换的。例如,已知,兰罗利珠单抗(lambrolizumab)也以替代和等同名称MK-3475和派姆单抗为人所知。
在一些实施方案中,PD-1结合拮抗剂是抑制PD-1与其配体结合配偶体结合的分子。在一个具体方面,PD-1配体结合配偶体是PDL1和/或PDL2。在另一个实施方案中,PDL1结合拮抗剂是抑制PDL1与其结合配偶体结合的分子。在一个具体方面,PDL1结合配偶体是PD-1和/或B7-1。在另一个实施方案中,PDL2结合拮抗剂是抑制PDL2与其结合配偶体结合的分子。在一个具体方面,PDL2结合配偶体是PD-1。拮抗剂可以是抗体、其抗原结合片段、免疫黏附蛋白、融合蛋白或寡肽。一些示例性抗体描述于美国专利No.8,735,553、8,354,509和8,008,449中,其均通过引用并入本文。用于本文中提供的方法的其他PD-1轴拮抗剂在本领域中是已知的,例如描述于美国专利公开No.US20140294898、US2014022021和US20110008369中,其均通过引用并入本文。
在一些实施方案中,PD-1结合拮抗剂是抗PD-1抗体(例如,人抗体、人源化抗体或嵌合抗体)。在一些实施方案中,抗PD-1抗体选自纳武单抗、派姆单抗和CT-011。在一些实施方案中,PD-1结合拮抗剂是免疫黏附蛋白(例如,包含与恒定区(例如,免疫球蛋白序列的Fc区)融合的PDL1或PDL2的细胞外或PD-1结合部分的免疫黏附蛋白)。在一些实施方案中,PD-1结合拮抗剂是AMP-224。纳武单抗(也称为MDX-1106-04、MDX-1106、ONO-4538、BMS-936558和)是WO2006/121168中描述的抗PD-1抗体。派姆单抗(也称为MK-3475、Merck3475、兰罗利珠单抗、/>和SCH-900475)是WO2009/114335中描述的抗PD-1抗体。CT-011(也称为hBAT或hBAT-1)是WO2009/101611中描述的抗PD-1抗体。AMP-224(也称为B7-DCIg)是WO2010/027827和WO2011/066342中描述的PDL2-Fc融合可溶性受体。
可在本文中提供的方法中被靶向的另一种免疫检查点是细胞毒性T淋巴细胞相关蛋白4(CTLA-4),也称为CD152。人CTLA-4的完整cDNA序列具有Genbank登录号L15006。CTLA-4见于T细胞表面上并且当与抗原呈递细胞表面上的CD80或CD86结合时用作“关闭”开关。CTLA4是免疫球蛋白超家族的成员,其在辅助性T细胞的表面上表达并向T细胞传递抑制信号。CTLA4与T细胞共刺激蛋白CD28类似,并且这两种分子与抗原呈递细胞上的CD80和CD86(也分别称为B7-1和B7-2)结合。CTLA4向T细胞传递抑制信号,而CD28传递刺激信号。细胞内CTLA4也见于调节性T细胞中并且可对其功能很重要。通过T细胞受体和CD28的T细胞激活导致CTLA-4(B7分子的抑制性受体)的表达提高。
在一些实施方案中,免疫检查点抑制剂是抗CTLA-4抗体(例如,人抗体、人源化抗体或嵌合抗体)、其抗原结合片段、免疫黏附蛋白、融合蛋白或寡肽。
可使用本领域中公知的方法来产生适用于本发明方法的抗人CTLA-4抗体(或从其来源的VH和/或VL结构域)。或者,可使用本领域公认的抗CTLA-4抗体。例如,在以下中公开的抗CTLA-4抗体可用于本文中公开的方法中:美国专利No.8,119,129;国际专利公开No.WO01/14424、WO 98/42752和WO 00/37504(CP675,206,也称为曲美目单抗;以前的ticilimumab);美国专利No.6,207,156;Hurwitz et al.,1998;Camacho et al.,2004;以及Mokyr et al.,1998。每个上述出版物的教导在此通过引用并入。也可使用与任何这些本领域公认的抗体竞争与CTLA-4结合的抗体。例如,国际专利申请No.WO2001014424和WO2000037504和美国专利No.US8,017,114中描述了人源化CTLA-4抗体;其均通过引用并入本文。
示例性的抗CTLA-4抗体是伊匹单抗(也称为10D1、MDX-010、MDX-101和)或其抗原结合片段和变体(参见例如WO 01/14424)。在另一些实施方案中,抗体包含伊匹单抗的重链和轻链CDR或VR。因此,在一个实施方案中,抗体包含伊匹单抗的VH区的CDRl、CDR2和CDR3结构域,以及伊匹单抗的VL区的CDR1、CDR2和CDR3结构域。在另一个实施方案中,抗体与上述抗体竞争与CTLA-4上的相同表位结合和/或结合至CTLA-4上的相同表位。在另一个实施方案中,抗体与上述抗体具有至少约90%的可变区氨基酸序列同一性(例如,与伊匹单抗具有至少约90%、95%或99%的可变区同一性)。
用于调节CTLA-4的其他分子包括例如美国专利No.5,844,905、5,885,796和国际专利申请No.WO1995001994和WO1998042752(其均通过引用并入本文)中描述的CTLA-4配体和受体,以及例如美国专利No.8,329,867(通过引用并入本文)中描述的免疫黏附蛋白。
4.手术
约60%患有癌症的人将经历某种类型的手术,其包括预防性、诊断性或分期、治愈性和姑息性手术。治愈性手术包括其中全部或一部分癌组织被物理去除、切除和/或破坏的切除术,并且可与其他治疗(例如本发明实施方案的治疗、化学治疗、放射治疗、激素治疗、基因治疗、免疫治疗和/或替代治疗)结合使用。肿瘤切除术是指物理去除至少一部分肿瘤。除肿瘤切除术之外,通过手术的治疗包括激光手术、冷冻手术、电外科手术和用显微镜控制的手术(莫氏手术(Mohs’surgery))。
在切除一部分或全部癌性细胞、组织或肿瘤之后,可在体内形成腔。治疗可通过灌注、直接注射或向该区域局部施用另外的抗癌治疗来实现。这样的治疗可以重复,例如每1、2、3、4、5、6或7天,或者每1、2、3、4和5周,或者每1、2、3、4、5、6、7、8、9、10、11或12个月。这些治疗也司具有多种剂量。
5.其他药剂
考虑可将另外的药剂与本发明实施方案的某些方面组合使用以改善治疗的治疗效力。这些另外的药剂包括影响细胞表面受体与GAP连接的上调的药剂、细胞抑制剂和分化剂、细胞黏附抑制剂、提高过度增殖细胞对细胞凋亡诱导剂或其他生物药剂之敏感性的药剂。通过提高GAP连接数提高细胞间信号转导将会提高相邻过度增殖细胞群的抗过度增殖性作用。在另一些实施方案中,细胞抑制剂或分化剂可与本发明实施方案的某些方面组合使用以改善治疗的抗过度增殖效力。考虑细胞黏附抑制剂以改善本发明实施方案的效力。细胞黏附抑制剂的一些实例是黏着斑激酶(focal adhesion kinase,FAK)抑制剂和洛伐他汀。进一步考虑提高过度增殖细胞对细胞凋亡之敏感性的其他药剂(例如抗体c225)可与本发明实施方案的某些方面组合使用以改善治疗效力。
IV.试剂盒
用于检测EGFR和/或HER2外显子20突变(例如本文中公开的那些)的试剂盒也在本公开内容的范围内。这样的试剂盒的一个实例可包含一组外显子20突变特异性引物。试剂盒可还包含用于使用引物以检测本文中所述的特定EFGR和/或HER2外显子20突变之存在或不存在的说明书。试剂盒可还包含用于诊断目的的说明书,指示在来自癌症患者的样品中本文中所述的EGFR和/或HER2外显子20突变的阳性鉴定表明对酪氨酸激酶抑制剂波齐替尼或阿法替尼或结构类似的抑制剂的敏感性。所述试剂盒可还包含说明书,其指示在来自癌症患者的样品中本文中所述的EGFR和/或外显子20突变的阳性鉴定表明患者应该用波齐替尼、阿法替尼或结构类似的抑制剂进行治疗。
V.实施例
包含以下实施例以示出本发明的一些优选实施方案。本领域技术人员应理解,在以下实施例中公开的技术表示本发明人发现的在本发明的实践中运行良好的技术,并因此可被认为构成用于其实施的一些优选模式。然而,根据本公开内容,本领域技术人员应理解,可对所公开的具体实施方案作出许多改变,并且仍然获得相似或类似的结果而不背离本发明的精神和范围。
实施例1-用于具有EGFR或HER外显子20插入之癌细胞的药物的鉴定
在临床数据库中患有具有EGFR外显子20插入的肿瘤的患者中研究针对TKI的临床响应;并且在用单一药剂厄洛替尼、吉非替尼或阿法替尼进行治疗的具有EGFR突变体NSCLC的280位患者中,129位患者被鉴定具有经典的EGFR突变(外显子19缺失、L858R和L861Q)并且9位患者具有EGFR外显子20插入。具有经典EGFR突变的NSCLC患者具有14个月的中位PFS,而具有EGFR外显子20插入的患者具有仅2个月的中位PFS(p<0.0001,对数秩检验;图1A)。在9位EGFR外显子20插入患者之中,在仅1位接受阿法替尼的携带S768del-insIL突变的患者中观察到OR(图4A)。该临床数据示出了可用的EGFR TKI在EGFR外显子20插入驱动的NSCLC中的有限活性,并验证了对于这些特定肿瘤需要替代治疗策略。
作为药物筛选中的初始步骤,在Ba/F3细胞中表达7种EGFR和11种HER2突变。EGFR和HER2外显子20突变的位置总结于图1B中。为了评估EGFR和HER2的哪些外显子20突变是激活的,筛选Ba/F3细胞系的IL-3非依赖性存活。发现测试的所有EGFR外显子20插入都是激活突变(图4B),6种HER2外显子20突变和位于外显子19中的L755P是激活突变(图4C)。接下来,测试外显子20插入对于已经经历了临床评价的EGFR和HER2TKI(包括可逆TKI(第一代)、不可逆TKI(第二代)和不可逆突变体特异性TKI(第三代))的敏感性,并随后与EGFR L858R(经典的敏感突变)的敏感性进行比较。除EGFR A763insFQEA之外,EGFR外显子20插入(n=6)对第一代(图1C,IC50=3.3至>10μM)、第二代(图1d,IC50=40至135nM)和第三代(图1e,IC50=103至850nM)EGFR TKI具有抗性(图5,表1)。此外,HER2外显子20突变体(n=6)对第一代(图1F,IC50=1.2至13μM)和第三代(图1H,IC50=114至505nM)TKI具有抗性。第二代TKI对Ba/F3HER2外显子20突变体细胞系具有一些活性(图1G,IC50=10至12nM,图6,表1)。与药物筛选一致,除了在较低剂量下显示部分抑制的EGFR A763insFQEA之外,Western印迹示出了厄洛替尼和奥希替尼不显著抑制EGFR外显子20插入突变中的p-EGFR2,并且仅在500nM下显著抑制HER2外显子20插入突变体中的p-HER2(图7A至7D)。
表1:EGFR/HER2 TKI对于EGFR和HER2外显子20插入的IC50值。
为了研究为什么外显子20插入对第一代和第三代EGFR TKI具有抗性,对于EGFRD770insNPG以及EGFR T790M和EGFR WT的解析晶体结构进行3D建模,以使药物结合袋内的变化可视化。该建模揭示了EGFR外显子20插入在看门残基(gatekeeper residue)T790的比对中与T790M突变相似,这导致对ATP的亲和力提高以及第一代抑制剂的结合降低,致使这些突变对非共价抑制剂具有抗性。此外,HER2外显子20插入诱导组成型活性构象,阻止非共价HER2抑制剂拉帕替尼的结合,后者以无活性构象与HER2结合。此外,EGFR和HER2外显子20插入对药物结合袋具有巨大的影响。EGFR(图1I)和HER2(图1J)外显子20插入的电脑模拟建模揭示了由于在α-c-螺旋的C末端处的插入所引起的α-c-螺旋显著移动进入药物结合袋中(箭头)(图1J),迫使α-c-螺旋在向内的激活位置中的脊状放置。此外,3D建模示出了P环显著移动进入这两种受体的药物结合袋中(图1I、1J)。这些移动一起导致EGFR和HER2外显子20突变体蛋白二者中来自两个方向的药物结合袋的空间位阻。与上述体外测试一致,3D建模支持阿法替尼比奥希替尼更有效地抑制外显子20插入的观察结果。奥希替尼具有直接连接至刚性嘧啶核心的大的末端1-甲基吲哚基团。这种大的非柔性基团降低了奥希替尼与阿法替尼一样有效地到达在EGFR外显子20插入中的C797残基的能力(图1I)。或者,阿法替尼具有通过仲胺基团间接连接至喹唑啉核的更小的1-氯-2-氟苯环末端基团,使得阿法替尼能够适合于空间上受阻的结合袋中。此外,空间位阻阻止了奥希替尼与HER2 A775insYVMA的结合。总之,体外数据和电脑模拟建模表明,小的柔性的喹唑啉衍生物能够靶向EGFR/HER2外显子20插入。
接下来寻求鉴定对外显子20插入具有增强活性的TKI。波齐替尼与阿法替尼一样,也包含小的末端基团和柔性的喹唑啉核心。然而,波齐替尼具有相比于阿法替尼更小的连接迈克尔(Michael)受体基团与喹唑啉核心的取代基以及相比于阿法替尼增强的末端苯环卤化。该富电子部分还与EGFR的碱性残基(例如K745)相互作用以进一步使其结合稳定化。因此,在Ba/F3系统中测试波齐替尼。在体外,波齐替尼强效地抑制EGFR外显子20突变体Ba/F3细胞系(图2A)和HER2外显子20突变体Ba/F3细胞(图2B)的生长。波齐替尼在EGFR外显子20突变体Ba/F3细胞系中具有1.0nM的平均IC50值,使得波齐替尼在体外比奥希替尼更强效约100倍,并且比阿法替尼更强效40倍。此外,波齐替尼在HER2外显子20突变体Ba/F3细胞系中具有1.9nM的平均IC50值,使得波齐替尼在体外比奥希替尼更强效200倍,并且比阿法替尼更强效6倍。这些结果通过Western印迹验证,其中波齐替尼在低至5nM的浓度下抑制EGFR和HER2的磷酸化(图2C、8A)。此外,为了验证波齐替尼敏感性不是由于EGFR或HER2突变体的表达水平,通过ELISA确定各个突变体的表达,然后对IC50值作图(图8D)。虽然在IC50与表达之间没有发现相关性(R=-0.056,p=0.856),但是在波齐替尼敏感性与EGFR的突变位置之间发现了相关性(R=0.687,p=0.044)(图2D),表明插入距离α-c-螺旋越远,IC50越高。有趣的是,对于HER2外显子20突变,未发现这种相关性,其在插入的尺寸而不是位置方面变化更大(图8E)。这种相关性表明突变的精确位置对药物结合袋具有不同的影响,导致所见到的药物响应的不均一性。此外,波齐替尼有效地抑制患者来源的细胞系CUTO14(EGFRA767dupASV)和YUL0019(EGFR N771del insFH)的生长,分别具有1.84nM和0.30nM的平均IC50值,其对于CUT014比阿法替尼更高效15倍,并且对于YUL0019比阿法替尼更高效超过100倍(图2E、2F)。CUT014细胞系的Western印迹确定了在10nM波齐替尼处理下p-EGFR的显著抑制,但通过阿法替尼直至1000nM才显著抑制p-EGFR(图8B、8C)。
为了确定相比于T790M突变体,波齐替尼抑制外显子20突变体的特异性,将阿法替尼、奥希替尼、罗西替尼和波齐替尼在外显子20突变体中的IC50值与阿法替尼、奥希替尼、罗西替尼和波齐替尼在EGFR T790M突变体Ba/F3细胞系中的IC50值进行比较。IC50值相对于单一EGFR T790M突变归一化示出,其中小于1的值表示相比于T790M对外显子20插入的特异性(图2G)。当与EGFR T790M突变体相比时,EGFR外显子20插入对波齐替尼敏感65倍。此外,与EGFR T790M突变体相比,EGFR外显子20插入突变对阿法替尼的抗性为1.4倍,对奥希替尼的抗性为5.6倍,并且对罗西替尼的抗性为24倍(图2G)。
为了检查与T790M突变相比,为什么波齐替尼而非第三代TKI(例如奥希替尼)选择性地且强效地抑制外显子20突变体,进行3D建模以确定药物结合袋中的变化如何影响药物结合。虽然奥希替尼适合于EGFRT790M突变体受体的药物结合袋中(图2H),但在外显子20突变体中,结合袋内的大的变化(图2I)在空间上阻碍第三代抑制剂的结合。然而,波齐替尼更小并且具有更大的柔性,使其适合于空间上受阻的外显子20结合袋中(图2I)。此外,对于EGFR D770insNPG与波齐替尼和阿法替尼的3D建模表明,P环移动进入药物结合袋中引起波齐替尼比阿法替尼更紧密地结合到药物结合袋中。结构建模的计算表明,波齐替尼的结合自由能(London ΔG)相比于阿法替尼更低,表明波齐替尼的结合亲和力更强。对于WT HER2与奥希替尼的3D建模示出WT HER2的结合袋大于HER2 A775insYVMA的结合袋。因此,波齐替尼紧密深入地结合到HER2A775insYVMA的空间上受阻的药物结合袋中,克服了由外显子20插入诱导的结构变化。
使用EGFR和HER2外显子20插入驱动的NSCLC的GEM模型在体内测试波齐替尼的效力。在先前描述的EGFR D770insNPG(Cho et al.,2013)和HER2 A775insYVMA(Perera etal.,2009)小鼠中诱导肺肿瘤,并且使动物每天经口接受波齐替尼(10mg/kg)或载剂对照持续4周。如通过MRI所确定的,波齐替尼在EGFR外显子20GEMM中使肿瘤负荷降低85%(图3A、3C),并且在HER2外显子20GEMM中降低60%(图3B、3D),抑制术平比先前在相同的GEM模型中对于阿法替尼所观察到的高37%。对于EGFR和HER2GEMM二者,示出了波齐替尼之前和之后的肿瘤的代表性MRI图像(图3C、3D)。在EGFR和HER2GEM二者模型中,用10mg/kg波齐替尼处理的小鼠表现出持久的消退,在12周时没有进展的迹象(图3E、3F)。此外,到14天时,在EGFR外显子20插入PDX模型LU0387(H773insNPH)中,波齐替尼处理(5或10mg/kg)使肿瘤完全减小(>85%抑制)(图3G)。
为了确定波齐替尼是否与其他不可逆抑制剂一样在C797处共价结合,产生具有在具奥希替尼抗性的患者的~30%中观察到的C797S突变的Ba/F3细胞系(Thress et al.,2015)。发现C797S突变诱导对波齐替尼的抗性,ICs0值>10μM。这些实验一起表明,波齐替尼可易感与其他第三代TKI类似的获得性抗性机制。
为了验证上述发现,使用具有HER2 G776del insVC的乳腺癌细胞系MCF10A进行实验。用不同的抑制剂在多种剂量下处理细胞,并且发现乳腺癌细胞系对波齐替尼敏感,如在所测试的其他细胞系中所见到的(图10)。因此,波齐替尼可用于治疗具有外显子20突变的其他癌症。
因此,发现外显子20突变体表现出对第一代、第二代和第三代TKI的新生抗性。使用EGFR D770insNPG和HER2 A775insYVMA的3D建模,波齐替尼被鉴定为具有可克服由外显子20中的插入诱导的药物结合袋内之变化的结构特征。此外,使用体外和体内模型证实了波齐替尼的预测活性,示出了波齐替尼在具有这些突变的细胞中的强效抗肿瘤活性。
发现在EGFR外显子20突变体中,波齐替尼比阿法替尼更强效约40倍,并且比达克替尼更强效65倍。此外,在体外在HER2外显子20突变体中,波齐替尼比阿法替尼和达克替尼更强效6倍。总之,这些数据表明尽管波齐替尼与阿法替尼和达克替尼共享相似的喹唑啉骨架,但相比于更常见的T790M突变,该激酶抑制剂的另外的特征导致对EGFR外显子20突变的提高的活性和相对特异性。
3D建模表明,波齐替尼的较小的尺寸、提高的卤化和柔性使得该抑制剂在外显子20突变体EGFR/HER2的空间上受阻的药物结合袋中具有竞争优势。在突变距离α-c-螺旋的距离与药物敏感性之间观察到负相关性。这种关系表明突变的精确位置影响药物结合袋和/或TKI的结合亲和力。此外,数据表明插入的尺寸也影响药物敏感性。此外,具有仅一个氨基酸的净增长的患者来源的细胞系YUL0019(N771del insFH)比具有更大的EGFR外显子20插入的细胞系对基于喹唑啉的泛HER抑制剂更敏感。
实施例2-材料和方法
患者群体和统计学分析:鉴定加入了前瞻性收集的MD Anderson Lung CancerMoon Shot GEMINI数据库的具有EGFR突变体NSCLC的患者。使用用于常规临床护理的50、134或409个基因的组的基于PCR的下一代测序之一确定EGFR突变状态。使用卡普兰-迈耶法(Kaplan Meier method)计算PFS。PFS被定义为从EGFR TKI的开始到放射学进展或死亡的时间。在治疗期间以6至8周的间隔获得再分期扫描(restaging scan),并根据1.1版实体瘤中的响应评鉴标准(Response Evaluation Criteria in Solid Tumor,RECIST)进行回顾性评估,以确定具有EGFR外显子20插入NSCLC的患者中的响应率。
细胞系产生和IL-3剥夺:在无菌条件下,在补充有L-谷氨酰胺、10%热灭活的FBS(Gibco)、1%青霉素/链霉素(Sigma Life Science)和10ng/ml小鼠IL-3(R&D systems)的完全RPMI-1640(R8758;Sigma Life Science)培养基中培养Ba/F3细胞系。通过逆转录病毒转导Ba/F3细胞系12小时产生稳定的细胞系。通过使用Lipofectamine 2000(Invitrogen)将表2中总结的基于pBabe-Puro的载体(Addgene和Bioinnovatise)转染到Phoenix 293T两性(ampho)包装细胞系(Orbigen)中产生逆转录病毒。在转导72小时之后,向培养基添加2μg/ml嘌呤霉素(Invitrogen)。在选择5天之后,将细胞用FITC-HER2(Biolegend)或PE-EGFR(Biolegend)染色并通过FACS进行分选。然后,在不存在IL-3的情况下将细胞系培养15天,并使用Cell Titer Glo测定法(Progema)每3天确定细胞生存力。将所得的稳定细胞系维持在不含IL-3的上述完全RPMI-1640培养基中。从ATCC获得HCC827和HCC4006肺癌细胞系,并将其在无菌条件下维持在10%RPMI培养基中。使用PowerPlex 1.2试剂盒(Promega)通过凭借短串联重复的DNA指纹分析证实细胞系身份。将指纹分析结果与由细胞系的原代来源维持的参考指纹进行比较。所有细胞系均不含支原体。为了产生厄洛替尼抗性细胞系,用提高浓度的厄洛替尼培养HCC827和HCC4006(两种EGFR突变体)细胞直至出现抗性变体。
表2:用于产生稳定细胞系的载体。
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细胞生存力测定和IC50评估:使用Cell Titer Glo测定法(Promega)确定细胞生存力。从混悬培养基收集细胞,在300×g下离心沉降5分钟并重悬于新鲜的RPMI培养基中,并使用Countess自动细胞计数器和锥虫蓝(Invitrogen)进行计数。技术上一式三份地以每孔1500个细胞接种在384孔板(Greiner Bio-One)中。用连续三倍稀释之TKI中的七种不同浓度的抑制剂或单独的载剂以40μL每孔的最终体积处理细胞。在72小时之后,添加11μLCellTiter Glo至每孔。将板摇动10分钟,并使用FLUOstar OPTIMA多模式微板读数器(BMGLABTECH)测定生物发光。将生物发光值相对于DMSO处理的细胞进行归一化,并在GraphPadPrism中使用非线性回归拟合为具有可变斜率的归一化数据将经归一化的值作图。通过GraphPad Prism在50%抑制下计算IC50值。除非指明,否则各个实验重复3次。
酪氨酸激酶抑制剂:拉帕替尼、阿法替尼、达克替尼、AZD9291、CO-1686、EGF816、依布替尼和HM781-36B购自Selleck Chemical。厄洛替尼和吉非替尼获自德克萨斯大学MD安德森癌症中心(The University of Texas MD Anderson Cancer Center)的机构药房。BI-694由Boehringer-Ingelheim提供。所有的抑制剂以10mM的浓度溶解在DMSO中并储存在-80℃下。
3D建模:检索EGFR D770insNPG蛋白的结构(蛋白质数据库进入代码:4LRM)并将其用作模板以构建EGFR D770insNPG的分子3D结构模型。使用Shen et al中先前公开的模型构建HER2 A775insYVMA。使用MODELLER 9v6构建同源性模型,并使用分子操作环境软件包(Molecular Operating Environment software package)(Chemical Computing Group,Montreal,Canada)进一步大力地最小化。除非另有说明,否则使用GOLD软件用默认参数进行TKI进入到外显子20突变体EGFR和HER2中的分子对接。在该对接过程中不允许提前终止。使用约束来模拟受体与抑制剂之间的共价键形成。使用GOLD软件来解决结合袋内残基的柔性。使用PYMOL使示出EGFR/HER2与抑制剂之间相互作用的图可视化。
Ba/F3突变体的Western印迹:对于Western印迹,将细胞在磷酸缓冲盐水中洗涤,并在蛋白质裂解缓冲液(ThermoFisher)和蛋白酶抑制剂混合物片剂(Roche)中裂解。将蛋白质(30至40μg)加载到购自BioRad的凝胶中。使用BioRad半干转移,并随后用针对pEGFR(#2234)、EGFR(#4267)、pHER2(#2247)、HER2(#4290)的抗体(1∶1000;Cell Signaling)探测。用针对β-肌动蛋白的抗体(Sigma-Aldrich,#A2228)或针对黏着斑蛋白的抗体(Sigma-Aldrich,#V4505)作为加载对照探测印迹,并使用SuperSignal West Pico化学发光底物(ThermoFisher)和BioRad的ChemiDoc触摸成像系统或射线照相胶片进行暴露。示出了两种独立的蛋白质分离物的代表性图像,并且以一式两份进行印迹分析。Western印迹的量化在Photoshop中完成并计算为(背景平均强度-样品平均强度)(像素数)=谱带强度。首先将样品相对于加载对照(β-肌动蛋白或黏着斑蛋白)归一化,然后相对于DMSO归一化并在GraphPad Prism中作图。在GraphPad Prism中计算来自DMSO的显著性。
Ba/F3突变体的ELISA和相关性:从亲本Ba/F3细胞系收获蛋白质,并且如上所述发现每个Ba/F3外显子20突变体是激活突变。如总EGFR(Cell signaling,#7250)和总HER2(Cell signaling,#7310)的制造说明书所述进行ELISA。将通过ELISA测定的相对表达对如上所述计算的IC50值作图。通过GraphPad Prism确定皮尔逊相关性和p值。
患者来源的细胞系研究:在知情同意之后,使用先前描述的培养方法(Davies etal.,2013),由患有肺腺癌的患者的胸腔积液产生CUTO14细胞。用指定剂量的阿法替尼或波齐替尼处理细胞系72小时,并通过MTS测定法(Promega)测定细胞生存力。如先前所述计算IC50(n=3)。如先前所述(Hong et al.,2007)完成患者来源的细胞系的Western印迹(n=3)。用指定剂量的阿法替尼或波齐替尼处理细胞2小时。除了总EGFR(BDTransductionLaboratories)和GAPDH(Calbiochem)之外,所有抗体均购自Cell Signaling Technology。
根据IRB批准的方案,由获自患有晚期肺腺癌的患者的恶性心包液建立YUL0019细胞系。将细胞系在补充有10%热灭活的胎牛血清(Atlanta Biologicals)和1%青霉素/链霉素(Corning)的RPMI+L-谷氨酰胺(Corning)中培养。为了证实EGFR突变的存在,使用RNeasy迷你试剂盒(Qiagen#74104)根据制造商的说明书从细胞沉淀中提取RNA。使用Superscript III First-Strand cDNA合成试剂盒(Invitrogen#18080-051)合成cDNA,并将其用作模板以扩增EGFR。通过Sanger测序使用以下引物对PCR产物进行测序:EGFR-2080F:CTTACACCC AGTGGAGAAGC(SEQ ID NO:5)和EGFR-2507RACCAAGCGACGGTCCTCCAA(SEQID NO:6)。人工查看正向和反向序列追踪。在患者来源的细胞系中检测到的变体是EGFR的外显子20中的复合插入(N771delinsFH),导致在位置771处的氨基酸天冬酰胺被两个氨基酸(苯丙氨酸和组氨酸)替代。如上所述进行细胞生存力和IC50评估。
患者来源的异种移植物(PDX)研究:由Crown BioSciences完成LU0387 PDX实验。简单地说,将来自表达EGFR H773insNPH的肿瘤的肿瘤碎片接种到5至6周龄雌性nu/nu裸小鼠中。当肿瘤达到100至200mm3时,将小鼠随机分成3组:5mg/kg波齐替尼,10mg/kg波齐替尼或载剂对照(在dH2O中的20%PEG-400、3%Tween-80)。每周两次测量肿瘤体积和体重。接受5mg/kg波齐替尼的小鼠接受药物4至5天,然后不给药4天,然后再接受给药4天。然后在不给药的情况下再观察小鼠2天。接受10mg/kg波齐替尼的小鼠接受药物3至4天,然后在不给药的情况下观察10天。从最终分析中排除由于与肿瘤负荷无关的事件被人为安乐死的小鼠。
基因工程小鼠模型(Genetically Engineered Mouse Model,GEMM)研究:如先前所述(Perera et al.,2009;Cho et al.,2013)产生EGFRD770insNPG和HER2 A775insYVMAGEMM。根据实验动物福利办公室(the Office of Laboratory Animal Welfare)定义的良好动物规范(Good Animal Practice)来处理小鼠,并在Dana-Farber癌症研究所机构动物护理和使用委员会(Dana-Farber Cancer Institute Institutional Animal Care andUse Committee)(Boston,MA)的批准下完成。小鼠从6周龄开始饲喂持续的多西环素饮食。如先前所述(Perera et al.,2009;Cho et al.,2013)通过MRI确定肿瘤体积。每天在通过MRI确定明显的肿瘤形成之后,将具有相等初始肿瘤体积的小鼠非盲随机分组至载剂和10mg/kg波齐替尼。从最终分析中排除由于与肿瘤负荷无关的事件被人类安乐死的小鼠。
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根据本公开内容,本文中公开且要求保护的所有方法均可在不进行过度实验的情况下做出和执行。虽然本发明的组合物和方法已根据一些优选实施方案进行描述,但是对于本领域技术人员来说将明显的是,在不偏离本发明的概念、精神和范围的情况下可对本文中所述方法以及本文中所述方法的步骤或步骤顺序作出改变。更具体地,将明显的是,在化学和生理学两方面都相关的某些试剂可替代本文中所述的试剂而实现相同或类似的结果。对本领域技术人员而言明显的所有这样的类似替代和修改被认为在由所附权利要求书限定的本发明的精神、范围和概念之内。
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序列表
<110> BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM
Robichaux, Jacqulyne
Nilsson, Monique
Heymach, John V
<120> 具有针对携带EGFR或HER2外显子20突变之癌细胞的抗肿瘤活性的化合物
<130> UTFC.P1306WO
<150> 62423732
<151> 2016-11-11
<150> 62427692
<151> 2016-11-29
<150> 62572716
<151> 2017-10-16
<160> 18
<170> PatentIn version 3.5
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<211> 4
<212> PRT
<213> 人工序列
<220>
<223> EGFR突变
<400> 1
Phe Gln Glu Ala
1
<210> 2
<211> 12
<212> DNA
<213> 人工序列
<220>
<223> EGFR突变
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tccaggaagc ct 12
<210> 3
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> HER2突变
<400> 3
Tyr Val Met Ala
1
<210> 4
<211> 12
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<213> 人工序列
<220>
<223> HER2突变
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tatgtcatgg ct 12
<210> 5
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<213> 人工序列
<220>
<223> 引物
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<213> 人工序列
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<220>
<223> EGFR外显子20 A763insFQEA
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gaagcctcca ggaagcctta cgtgatggcc agcagcgtgg acgtggacaa cccccacgtg 60
tgccgc 66
<210> 9
<211> 45
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<213> 人工序列
<220>
<223> EGFR外显子20 S768dupSVD
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gaagcctacg tgatggccag cgtggacaac ccccacgtgt gccgc 45
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<212> DNA
<213> 人工序列
<220>
<223> EGFR外显子20 V769insASV
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gaagcctacg tgatggccag cgtgccagcg tgggacaacc cccacgtgtg ccgc 54
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<212> DNA
<213> 人工序列
<220>
<223> EGFR外显子20 D770insSVD
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gaagcctacg tgatggccag cgtggacgcg tggacaaacc cccacgtgtg ccgc 54
<210> 12
<211> 54
<212> DNA
<213> 人工序列
<220>
<223> EGFR外显子20 H773insNPH
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Claims (19)
1.波齐替尼用于制备用于在对象中治疗癌症的药物的用途,其中所述药物配制成用于向所述对象施用有效量的波齐替尼,其中所述对象患有已被确定具有一个或更多个EGFR外显子20插入突变的肿瘤,其中所述一个或更多个EGFR外显子20插入突变包含第763至778位氨基酸之间1至6个氨基酸的插入,其中所述一个或更多个EGFR外显子20插入突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、N771delinsFH和H773insNPH,其中所述对象已被确定不具有C797或T790 EGFR突变。
2.权利要求1所述的用途,其中所述对象已被确定具有2、3或4个EGFR外显子20突变。
3.权利要求1所述的用途,其中所述外显子20插入突变是D770insNPG。
4.权利要求1所述的用途,其中通过分析来自患者的基因组样品,所述对象被确定具有EGFR外显子20插入突变。
5.权利要求4所述的用途,其中所述基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。
6.权利要求1所述的用途,其中通过核酸测序或PCR分析来确定EGFR外显子20插入突变的存在。
7.权利要求1所述的用途,其中所述药物配制成还用于施用另外的抗癌治疗。
8.权利要求7所述的用途,其中所述另外的抗癌治疗是化学治疗、放射治疗、基因治疗、手术、激素治疗、抗血管生成治疗或免疫治疗。
9.权利要求7所述的用途,其中所述波齐替尼和/或抗癌治疗配制成用于静脉内、皮下、骨内、经口、经皮、以持续释放、以受控释放、以延迟释放、作为栓剂或舌下施用。
10.权利要求7所述的用途,其中施用所述波齐替尼和/或抗癌治疗包括局部、区域或全身施用。
11.权利要求7所述的用途,其中所述波齐替尼和/或抗癌治疗配制成用于施用两次或更多次。
12.权利要求1所述的用途,其中所述癌症是口腔癌、口咽癌、鼻咽癌、呼吸系统癌症、泌尿生殖系统癌症、胃肠癌、中枢或周围神经系统组织癌症、内分泌或神经内分泌癌或造血系统癌症、胶质瘤、肉瘤、上皮癌、淋巴瘤、黑素瘤、纤维瘤、脑脊膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、利-弗劳梅尼肿瘤、甲状腺癌、甲状旁腺癌、垂体肿瘤、肾上腺肿瘤、成骨肉瘤肿瘤、多发性神经内分泌I型和II型肿瘤、乳腺癌、肺癌、头颈癌、前列腺癌、食管癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌。
13.权利要求1所述的用途,其中所述癌症是非小细胞肺癌。
14.权利要求1所述的用途,其中患者是人。
15.用于检测基因组样品中的EGFR外显子20插入突变的试剂用于制备用于在患有癌症的对象中预测对单独的或与第二抗癌治疗组合的波齐替尼的响应的试剂盒的用途,其中所述试剂盒配制成用于检测获自所述患者的基因组样品中的EGFR外显子20插入突变,其中如果所述样品对于所述EGFR外显子20插入突变的存在呈阳性,则预测所述患者具有对所述单独的或与抗癌治疗组合的波齐替尼的有利响应,其中一个或更多个EGFR外显子20插入突变包含第763至778位氨基酸之间1至6个氨基酸的插入,其中所述一个或更多个EGFR外显子20插入突变选自A763insFQEA、A767insASV、S768dupSVD、V769insASV、D770insSVD、D770insNPG、N771del insFH和H773insNPH,其中所述对象已被确定不具有C797或T790EGFR突变。
16.权利要求15所述的用途,其中所述基因组样品从唾液、血液、尿、正常组织或肿瘤组织中分离。
17.权利要求15所述的用途,其中通过核酸测序或PCR分析来确定EGFR外显子20插入突变的存在。
18.权利要求15所述的用途,其中对单独的或与抗癌治疗组合的波齐替尼的有利响应包括减小肿瘤尺寸或负荷、阻断肿瘤生长、减轻肿瘤相关疼痛、减轻癌症相关病理状况、减轻癌症相关症状、癌症无进展、延长无疾病间隔、延长进展时间、诱导缓解、降低转移或延长患者存活。
19.权利要求15所述的用途,其中所述药物配制成还用于向预期具有有利响应的所述患者施用单独的或与第二抗癌治疗组合的波齐替尼。
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CN110291104A (zh) | 2019-09-27 |
JP2023100682A (ja) | 2023-07-19 |
CU20190051A7 (es) | 2020-01-03 |
CA3044432A1 (en) | 2018-05-24 |
US20200316071A1 (en) | 2020-10-08 |
US11446302B2 (en) | 2022-09-20 |
PH12019501116A1 (en) | 2019-11-25 |
MX2019005834A (es) | 2019-10-14 |
AU2023266384A1 (en) | 2023-12-07 |
EP3541832A4 (en) | 2020-09-30 |
CL2019001353A1 (es) | 2019-11-08 |
EP3541832A1 (en) | 2019-09-25 |
AU2017363199B2 (en) | 2023-08-17 |
PE20191303A1 (es) | 2019-09-23 |
MA46852A (fr) | 2019-09-25 |
BR112019010020A2 (pt) | 2019-08-20 |
TWI782931B (zh) | 2022-11-11 |
AU2017363199A1 (en) | 2019-07-04 |
WO2018094225A1 (en) | 2018-05-24 |
KR20230145496A (ko) | 2023-10-17 |
JP7265985B2 (ja) | 2023-04-27 |
KR20190085980A (ko) | 2019-07-19 |
ECSP19043254A (es) | 2019-09-30 |
CO2019006218A2 (es) | 2020-01-17 |
CN117599061A (zh) | 2024-02-27 |
TW201825098A (zh) | 2018-07-16 |
JP2020502059A (ja) | 2020-01-23 |
US20230233563A1 (en) | 2023-07-27 |
KR102585006B1 (ko) | 2023-10-05 |
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