CN113244205A - 多发性骨髓瘤的治疗 - Google Patents
多发性骨髓瘤的治疗 Download PDFInfo
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- CN113244205A CN113244205A CN202110534021.1A CN202110534021A CN113244205A CN 113244205 A CN113244205 A CN 113244205A CN 202110534021 A CN202110534021 A CN 202110534021A CN 113244205 A CN113244205 A CN 113244205A
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- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
本发明总体涉及多发性骨髓瘤的治疗。本发明的一个实施方式提供了曲古抑菌素A(TSA)在制备用于治疗过表达至少一种基因的多发性骨髓瘤(MM)的药物中的应用，所述至少一种基因选自由CCNB1、TOP2A、KIF11和WEE1组成的组，其中，曲古抑菌素A在所述药物中是所述至少一种基因的唯一抑制剂；并且其中，所述药物足以降低过表达的所述至少一种基因的表达。
Description
本申请是分案申请，其原申请的申请号为201480046344.4，申请日为2014年8月22日，发明名称为“多发性骨髓瘤的治疗”。
相关申请的交叉引用
本申请要求共同未决的2013年8月22日提交的61/869,039号美国临时专利申请和2013年8月27日提交的61/870,747号美国临时专利申请的权益，并将其各自并入本文。
技术领域
本发明涉及曲古抑菌素A(TSA)在制备用于治疗过表达一种或多种基因的多发性骨髓瘤(MM)的药物中的应用。
背景技术
多发性骨髓瘤(MM)(有时也被称为浆细胞骨髓瘤)是骨骼***中的多病灶浆细胞癌，一般影响老年个体。大多数个体在诊断时具有症状，所述诊断通常是通过血清蛋白电泳、血清游离κ/λ轻链化验、尿蛋白电泳(99％的MM患者表现出血液中免疫球蛋白(Ig)类别和/或尿液中轻链中的一种的水平增加)、骨髓检查或X-射线分析中的一种或多种来进行的。虽然MM一般对化疗有响应，但复发是常见的，因为这种治疗不是以癌症干细胞为靶标的。
Nara等人最近鉴定出了用于靶向MM肿瘤引发亚群(SP)细胞(即，癌症干细胞)的多种候选基因。这些候选基因包括编码与细胞周期和有丝***相关的蛋白的多种基因，发现所有这些基因在MM细胞中上调。这些基因包括细胞周期蛋白B1(CCNB1)、细胞***周期2(CDC2)、包含杆状病毒IAP重复序列的蛋白5(BIRC5)、与小头畸形相关的异常纺锤体同系物(ASPM)、拓扑异构酶(DNA)IIα170kDa(TOP2A)、极光激酶B(AURKB)、驱动蛋白家族成员11(KIF11)和驱动蛋白家族成员2c(KIF2C)。
类似地，Shaughnessy等人报告了针对多发性骨髓瘤的70种基因高危谱。在该高危谱中上调的两种基因是CDC28蛋白激酶调节亚基1B(CKS1B)和WEE1同系物(S.pombe)(WEE1)。
发明内容
本发明的一个实施方式提供了一种治疗个体的多发性骨髓瘤(MM)的方法，该方法包括：对所述个体施用有效量的曲古抑菌素A(TSA)。
在另一个实施方式中，本发明提供了一种治疗个体的多发性骨髓瘤(MM)的方法，该方法包括：由从个体的身体获得的生物样品确定至少一种基因的表达水平，所述基因选自由CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B和WEE1组成的组；并且在所述至少一种基因的表达水平表明过表达的情况下，对所述个体施用有效量的曲古抑菌素A(TSA)。
在另一个实施方式中，本发明提供了一种治疗个体的多发性骨髓瘤(MM)的方法，该方法包括：诊断或已经诊断所述个体患有MM；和对所述个体施用有效量的曲古抑菌素A(TSA)。
在另一个实施方式中，本发明提一种药物组合物，其包含：曲古抑菌素A(TSA)，其作为CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B、或WEE1的唯一或主要抑制剂；和药学上可接受的赋形剂或载剂。
在本发明的其它实施方式中，利用TSA进行的治疗与一种或多种其它多发性骨髓瘤治疗相结合。此种其它治疗可以包括例如小分子抑制。
具体实施方式
曲古抑菌素A(TSA或7-[4-(二甲基氨基)苯基]-N-羟基-4,6-二甲基-7-氧代庚-2,4-二烯酰胺)是一种抗真菌的抗菌素。曲古抑菌素A的结构在下式I中示出。
申请人已经惊讶的发现，TSA虽然先前已知为I类和II类组蛋白脱乙酰基酶(HDAC)抑制剂，但其也能够抑制CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B和WEE1的表达。因此，TSA在MM的治疗中可以用作一种或多种此类基因的主要或唯一的抑制剂。
用曲古抑菌素或载质处理人视网膜色素上皮细胞系24小时，并且使用Affymetrix仪器生成覆盖12,490种基因的22,238个探针集的基因表达。曲古抑菌素A对CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B和WEE1表达的影响在下表1中示出，并且表明了各基因表达的显著下调。
表1
这些结果支持了TSA在MM治疗中的应用。例如，通过向个体施用有效量的TSA，可对个体的MM进行治疗，其中所述有效量是足以抑制所述个体中的CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B和WEE1中一种或多种的表达的量。此量也可足以抑制个体中的HDAC活性。在本发明的一些实施方式中，所述有效量为约0.01mg/kg/日～约100mg/kg/日，例如，约0.1mg/kg/日～约10mg/kg/日，或约0.5mg/kg/日～约5mg/kg/日。
在一些实施方式中，对个体的治疗可以进一步包括：由从个体的身体获得的生物样品确定CCNB1、AURKB、CDC2、BIRC5、KIF11、KIF2C、TOP2A、ASPM、CKS1B或WEE1中一种或多种的表达水平。此种确定可以包括任何已知的或以后开发的方法或技术，包括例如定量抗原-抗体相互作用、示踪核苷酸探针的使用等。
在本发明的其它实施方式中，对个体的治疗可以包括：诊断或已经诊断所述个体患有MM，而后对所述个体施用TSA。此种诊断可以包括用于进行这种诊断的一种或多种技术或方法，包括例如血清蛋白电泳、血清游离κ/λ轻链化验、尿蛋白电泳、骨髓检查或X射线分析。
可将TSA以药物组合物的形式施用至待治疗的个体。根据本发明各实施方式使用的药物组合物包括：治疗有效量的TSA或TSA的活性代谢物，或其药学上可接受的盐或其它形式(例如，溶剂化物)，以及一种或多种药学上可接受的赋形剂或载剂。短语“药物组合物”是指适合于在医疗应用中施用的组合物。应当理解的是，为特定患者确定适宜的剂型、剂量和施用途径是在制药和医疗领域的普通技术人员的水平之内的。
施用可以是口服的，但也可以采用其它施用途径，例如，肠胃外、经鼻、经颊、经皮、舌下、肌内、静脉内、直肠、***等。用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在此种固体剂型中，将化合物与至少一种惰性的药学上可接受的赋形剂混合，所述赋形剂如为：(a)填充剂或膨胀剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(e)溶液缓凝剂，例如石蜡；(f)吸收促进剂，例如季铵类化合物；(g)润湿剂，例如，鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土和膨润土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或它们的混合物。在胶囊、片剂和丸剂的情况下，所述剂型也可以包括缓冲剂。诸如片剂、糖锭剂、胶囊、丸剂和颗粒剂等固体剂型也可以制备有包衣和外壳，例如肠溶包衣和本领域公知的其它包衣和外壳。固体剂型还可以含有遮光剂，并且也可以具有在肠道的某一部分内以延时方式释放一种或多种活性化合物的组成。可以使用的包埋组合物的实例是聚合物和蜡。适当的时候，活性化合物也可以是具有一种或多种上述赋形剂的微囊封装形式。这些固体剂型一般可以含有1％～95％(w/w)的活性化合物。在某些实施方式中，所述活性化合物为5％～70％(w/w)。
用于口服施用的固体组合物可以以单位剂型配制，每一剂量含有约0.1mg～约5000mg的活性成分。术语“单位剂型”是指适合作为用于人受试者和其它哺乳动物的单元剂量的物理上离散的单位，每个单位含有与所需药物载剂结合的预定量的活性成分，所述预定量的活性成分经计算能够在治疗期间产生所需的效果。TSA可以被配制成例如这样的单位剂型：其是具有赋形剂和0.1mg～5000mg活性成分的胶囊。
用于口服施用的液体剂型包括药学上可接受的乳剂、溶液、悬浮液、糖浆和酏剂。除了该化合物或组合物，所述液体剂型可以含有本领域中常用的惰性稀释剂，比如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇类和山梨聚糖的脂肪酸酯，或这些物质的混合物。除了这些惰性稀释剂，所述组合物还可以包括佐剂，例如润湿剂、乳化剂和悬浮剂、增甜剂、调味剂和芳香剂。
在本发明的一些实施方式中，TSA以液体形式提供，并且静脉内地施用至个体。根据本发明的一些实施方式，TSA以缓释或控释制剂形式提供。
虽然已结合以上概述的具体实施方式描述了本发明，但很明显，许多替换、修改和变型对本领域技术人员而言是显而易见的，或者旨在以其它方式涵盖在内。因此，如上所述的本发明的实施方式旨在为说明性的，不是限制性的。在不脱离下面权利要求书所限定的本发明的主旨和范围的情况下，可以进行各种改变。本文引用的所有专利、专利申请、科学论文和其他发表的文献以其公开的实质内容而整体并入本文。
Claims (7)
1.曲古抑菌素A(TSA)在制备用于治疗过表达至少一种基因的多发性骨髓瘤(MM)的药物中的应用，所述至少一种基因选自由CCNB1、TOP2A、KIF11和WEE1组成的组，
其中，曲古抑菌素A在所述药物中是所述至少一种基因的唯一抑制剂；并且
其中，所述药物足以降低过表达的所述至少一种基因的表达。
2.如权利要求1所述的应用，其中，所述药物足以降低选自由AURKB、CDC2、BIRC5、KIF2C和CKS1B组成的组的至少一种额外基因的表达。
3.如权利要求2所述的应用，其中所述药物足以降低所述个体中的CCNB1基因和/或AURKB基因的表达。
4.如权利要求2所述的应用，其中所述药物足以降低CKS1B基因和/或WEE1基因的表达。
5.如权利要求2所述的应用，其中所述药物足以降低CCNB1基因、AURKB基因、CDC2基因、BIRC5基因、KIF11基因、KIF2C基因、TOP2A基因、ASPM基因、CKS1B基因和WEE1基因的每个的表达。
6.如权利要求1所述的应用，其中，所述药物被配制成用于口服施用。
7.如权利要求1所述的应用，其中，所述药物被配制成用于静脉内施用。
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| CN109913420A (zh) * | 2019-03-07 | 2019-06-21 | 北京师范大学 | Cdc20共表达基因网络作为胶质瘤治疗靶点的应用 |
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