CN111733235A - Kdm5a基因和atrx基因的应用 - Google Patents

Kdm5a基因和atrx基因的应用 Download PDF

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CN111733235A
CN111733235A CN202010211409.3A CN202010211409A CN111733235A CN 111733235 A CN111733235 A CN 111733235A CN 202010211409 A CN202010211409 A CN 202010211409A CN 111733235 A CN111733235 A CN 111733235A
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kdm5a
atrx
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lung cancer
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鲁先平
山松
潘德思
宁志强
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Abstract

本发明涉及药物技术领域，公开了KDM5A基因和ATRX基因的应用。本发明通过以患者的无进展生存期(PFS)和客观缓解率(ORR)作为疗效指标，验证了KDM5A基因和ATRX基因变异与西奥罗尼疗效的关联性，对KDM5A基因和ATRX基因突变信息的检测，可以指导西奥罗尼的临床用药和评价其对小细胞肺癌的疗效。

Description

KDM5A基因和ATRX基因的应用
本申请要求于2019年3月25日提交中国专利局、申请号为201910228411.9、发明名称为“KDM5A基因和ATRX基因的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物技术领域，具体涉及KDM5A基因和ATRX基因的应用。
背景技术
肺癌发病率及死亡率均高居恶性肿瘤第一位，小细胞肺癌(small cell lungcancer，SCLC)占肺癌总数的10％～15％，其临床特点和生物学行为异于其他类型肺癌，表现为倍增时间短，早期易发生转移，恶性程度极高。未接受治疗的患者常在2～4个月内死亡，尽管初治患者对化疗较敏感，但很容易产生耐药性和复发，且对二线化疗药物相对不敏感，预后较差。确诊30％～40％的患者处于局限期，60％～70％的患者处于广泛期。局限期长期生存率在20％，广泛期则在2％。
依托泊苷/顺铂(EP)方案是目前SCLC主要化疗方案，III期临床研究结果显示，在局限期SCLC患者中，EP方案的2年和5年生存率优于环磷酰胺/表阿霉素/长春新碱方案(25％比10％，8％比3％)；对于广泛期SCLC患者，EP方案同样可以带来生存获益。后续的一系列研究亦证实了EP方案的有效性，因此EP方案成为SCLC的标准一线化疗。
伊立替康/顺铂(CPT-11/DDP，IP)方案组和EP方案组，结果显示，两组患者的客观缓解率(ORR)分别为84.4％、67.5％(P＝0.02)，中位生存期分别为12.8个月、9.4个月(P＝0.002)。拓扑替康联合最佳支持治疗组总生存期、生活质量及症状的改善均明显优于单用最佳支持治疗组，拓扑替康也成为SCLC的二线化疗药物。总体而言，SCLC缺乏有效的治疗手段，在常规EP或IP方案失败后，二线可选方案较少(如拓扑替康、紫杉醇等)，且二线治疗失败后，NCCN等指南只推荐支持治疗或临床研究。因此小细胞肺癌，需要探寻更高疗效的治疗方案。
发明内容
有鉴于此，本发明的目的在于提供KDM5A基因和/或ATRX基因作为生物标志物在评价西奥罗尼疗效或指导西奥罗尼用药中的应用。
中文通用名为西奥罗尼的化合物目前处于临床试验阶段，其化学名为N-(2-氨基苯基)-6-(7-甲氧基喹啉-4-氧)-1-萘酰胺，其结构式如式(I)所示：
Figure BDA0002421761460000021
本发明以西奥罗尼胶囊针对复发难治的小细胞肺癌进行Ib期临床试验，通过对血浆游离肿瘤DNA(ctDNA)的检测分析，对548个肿瘤相关基因进行了疗效相关生物标志物的伴随研究。所有患者在入组前均提取血液样品，对肿瘤相关基因的基因序列检测，包括基因突变和拷贝数异常。检测结果选取了所有突变发生率0.4％以上的基因，以患者的无进展生存期(PFS)和客观缓解率(ORR)作为疗效指标，分析肿瘤相关基因异常与西奥罗尼疗效的关联性。结果显示，在548个肿瘤相关基因中，只有KDM5A基因和ATRX基因与西奥罗尼疗效有显著的关联性。
具体试验结果表明，KDM5A基因和ATRX基因的变异分别与西奥罗尼在小细胞肺癌患者中的PFS和ORR存在显著相关性。其中，中位PFS在KDM5A基因突变患者中为145天，野生型患者中为27.5天，P值为0.0087；在以客观缓解(PR)和非缓解(SD+PD)作为疗效评价指标时，ATRX基因突变患者的疗效评价显著优于野生型患者，P值为0.0031。
根据上述技术效果，本发明还对应提出了检测KDM5A基因和/或ATRX基因变异的产品在制备评价西奥罗尼疗效或指导西奥罗尼用药的产品中的应用；以及KDM5A基因和/或ATRX基因在制备评价西奥罗尼疗效或指导西奥罗尼用药的生物标志物中的应用。
此外，本发明还提供一种评价西奥罗尼疗效或指导西奥罗尼用药的方法，对小细胞肺癌肿瘤组织进行基因突变的检测，若KDM5A基因或ATRX基因存在基因突变，则西奥罗尼的疗效较佳。
在本发明具体实施方式中，以小细胞肺癌肿瘤组织ctDNA为检测样品，采用二代测序技术检测；基因突变的检测手段有多种，并不局限于具体实施中对ctDNA的二代测序技术检测，对肿瘤组织、肿瘤循环细胞或人体其它来源的样品，采用基因测序、PCR、FISH、免疫组化等其它检测手段，均可实现对基因突变的检测。
由以上技术方案可知，本发明通过以患者的无进展生存期(PFS)和客观缓解率(ORR)作为疗效指标，验证了KDM5A基因和ATRX基因变异与西奥罗尼疗效的关联性，对KDM5A基因和ATRX基因突变信息的检测，可以指导西奥罗尼的临床用药和评价其对小细胞肺癌的疗效，特别适用于难治、复发的小细胞肺癌。
具体实施方式
本发明公开了KDM5A基因和ATRX基因的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。
以下就本发明所提供的KDM5A基因和ATRX基因的应用做进一步说明。
实施例1：西奥罗尼单药治疗复发难治的小细胞肺癌的Ib期临床试验
试验药物：西奥罗尼胶囊，规格：5mg、25mg。由深圳微芯生物科技股份有限公司生产。
给药方案：西奥罗尼胶囊按50mg/天、QD给药(对体重或体表面积不做调整)。每天上午空腹服用，用水送服，完整吞服整粒胶囊。连续给药28天为1个治疗周期，每个治疗周期间无间隔。
病例数：入组25例。
入选标准：
1、年龄≥18岁，≤75岁，性别不限；
2、组织学或细胞学证实的小细胞肺癌；
3、既往至少接受过2种不同的系统化疗方案(其中包括含铂化疗方案)后均出现疾病进展或复发；
4、根据RECIST1.1标准，至少有一个可测量的靶病灶，放疗或局部区域治疗的病灶必须有疾病进展的影像学证据方可视为靶病灶；
5、ECOG体力评分0-1分；
6、主要器官功能符合以下标准：
血常规：中性粒细胞绝对值≥1.5×109/L，血小板≥75×109/L，血红蛋白≥80g/L；
血生化：总胆红素≤正常值上限的1.5倍，AST/ALT≤正常值上限的2.5倍(若肝转移，则≤正常值上限的5倍)，血清肌酐≤正常值上限的1.5倍；
凝血功能：凝血酶原时间-国际标准化比率(PT-INR)<1.5。
7、预期生存时间≥3个月；
8、自愿签署书面知情同意书。
治疗计划：
试验受试者每天口服西奥罗尼胶囊50mg一次，每28天为一个治疗周期，治疗周期间无停药间隔期。整个试验期间，所有受试者均持续治疗直至出现以下任一情况(以先发生者为准)：疾病进展、不能耐受的毒性反应、死亡、撤回知情同意或失访。
疗效评估：根据RECIST1.1标准，分别在基线期以及治疗后第4周末评估一次，后续每8周重复进行，直到疾病进展。肿瘤影像学检查包括颈部、胸部、全腹、盆腔CT或MRI，其他部位检查根据临床指征，有需要时进行，病灶基线和后续评估测量应采用同样的技术和方法。
安全性评估：包括体格检查、生命体征、ECOG体能评分、血常规、尿常规、12导联ECG、血生化、电解质、凝血功能、心肌酶、肌钙蛋白、TSH、FT3、FT4、淀粉酶、超声心动图、24小时尿蛋白定量(必要时)、不良事件。
生物标志物研究：
在受试者首次服用西奥罗尼前和疾病进展时取外周血10毫升，对血浆游离肿瘤DNA(ctDNA)和白细胞提取DNA(对照)进行基因序列的检测，共包括548个肿瘤相关基因，检测结果包括基因突变和拷贝数异常，以及对肿瘤突变负荷(TMB)的分析。
临床试验结果：
入组患者25例，有疗效评价的患者20例，其中有4例患者的最佳疗效评价为部分缓解(PR)，ORR为20％，获益率60％。结果显示西奥罗尼单药治疗小细胞肺癌有效。
对已评价患者血浆游离肿瘤DNA(ctDNA)检测分析，对548个肿瘤相关基因进行了疗效相关生物标志物的伴随研究。检测结果选取了所有突变发生率0.4％以上的基因，以患者的无进展生存期(PFS)和客观缓解(PR)作为疗效指标，分析肿瘤相关基因异常与西奥罗尼疗效的关联性。结果显示，在548个肿瘤相关基因中，只有KDM5A基因和ATRX基因与西奥罗尼疗效有显著的关联性。
KDM5A基因与患者无进展生存期(PFS)获益存在显著相关性，结果见表1。
表1
Figure BDA0002421761460000051
表1结果显示，以患者的无进展生存期(PFS)作为疗效评价指标，KDM5A基因突变与患者PFS获益存在显著相关性。KDM5A基因野生型患者共12例，中位PFS为27.5天；KDM5A基因突变型患者共8例，中位PFS为145天。KDM5A基因突变患者和野生型患者无进展生存期存在显著统计学差异，P值为0.0087。表明KDM5A基因突变型患者在西奥罗尼治疗中能获得更好的获益。
ATRX基因与患者客观缓解(PR)获益存在显著相关性，结果见表2。
表2
Figure BDA0002421761460000052
表2结果显示，在以客观缓解(PR)和非缓解(SD+PD)作为疗效评价指标时，ATRX基因突变患者共6例，其中出现客观缓解评价病例4例，占全部突变患者的66.7％，ATRX基因野生型患者共14例，出现客观缓解评价病例0例，占全部野生型患者的0％。ATRX基因突变患者和野生型患者客观缓解情况存在显著统计学差异，P值为0.0031。以上结果表明ATRX基因突变型患者在西奥罗尼治疗中能获得更好的客观缓解获益。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (8)

1.KDM5A基因和/或ATRX基因作为生物标志物在评价西奥罗尼疗效或指导西奥罗尼用药中的应用。
2.检测KDM5A基因和/或ATRX基因变异的产品在制备评价西奥罗尼疗效或指导西奥罗尼用药的产品中的应用。
3.KDM5A基因和/或ATRX基因在制备评价西奥罗尼疗效或指导西奥罗尼用药的生物标志物中的应用。
4.一种评价西奥罗尼疗效或指导西奥罗尼用药的方法，其特征在于，对小细胞肺癌肿瘤组织进行基因突变的检测，若KDM5A基因或ATRX基因存在基因突变，则西奥罗尼的疗效较佳。
5.根据权利要求4所述方法，其特征在于，所述检测以ctDNA、肿瘤组织、肿瘤循环细胞或人体其它来源的组织为检测样品。
6.根据权利要求4所述方法，其特征在于，所述检测以基因测序、PCR、FISH、免疫组化、ELISA、Western或流式细胞技术为检测方法。
7.西奥罗尼在治疗KDM5A基因或ATRX基因存在基因突变的小细胞肺癌患者中的用途。
8.西奥罗尼在制备用于治疗KDM5A基因或ATRX基因存在基因突变的小细胞肺癌患者的药物中的用途。
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