CN107137406B - 一种Hedgehog信号通路抑制剂在制备治疗EGFR过度表达的癌症的药物中的用途 - Google Patents
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Abstract
一种Hedgehog信号通路抑制剂在制备治疗EGFR过度表达的癌症的药物中的用途。所述Hedgehog信号通路抑制剂还可以与EGFR抑制剂联合使用。本发明还涉及包含上述两种抑制剂的药物组合物。
Description
技术领域
本发明涉及一种Hedgehog抑制剂在制备治疗EGFR过度表达的癌症中的用途药物中的用途。
背景技术
肺癌是发病率和死亡率增长最快，对人群健康和生命威胁最大的恶性肿瘤之一。2015年中国预计有429.2万例新发肿瘤病例和281.4万例死亡病例。肺癌是发病率最高的肿瘤，也是癌症死因之首。男性肺癌发病率和死亡率均占所有恶性肿瘤的第一位，女性发病率占第二位，死亡率占第二位。
表皮生长因子受体的酪氨酸酶抑制剂(EGFR-TKI)在目前治疗非小细胞肺癌(NSCLC)分子靶向治疗中应用最广、最成功的一类药物，目前市场上已有多种EGFR-TKI类药物销售，如吉非替尼、厄洛替尼、阿法替尼、埃克替尼等，对EGFR基因敏感突变的非小细胞肺癌的有效率达到70％以上。但是，几乎所有患者将会发生耐药、疾病进展。针对EGFR-TKI耐药，目前还没有标准的治疗方法。
CN103261198A公开了一类Hedgehog信号通路抑制剂，其中包括如下式(I)的化合物，其化学名为N-(2-乙基-5-(6-(2-(三氟甲基)吡啶-3-基)咪唑并[1,2-b]哒嗪-2-基)苯基)-1-甲基环丙基甲酰胺，并公开了Hedgehog信号通路可能与胶质母细胞瘤、基底细胞癌以及胰腺癌有关。并没有任何文献提到此类Hedgehog信号通路抑制剂与EGFR-TKI耐药的癌症有何关联。
发明内容
本发明惊奇地发现，Hedgehog信号通路抑制剂对于EGFR阳性(或过度表达)的癌症有良好的治疗作用。优选地，所述的Hedgehog信号通路抑制剂为如下式(I)所示化合物或其可药用盐。本发明中，所述的Hedgehog信号通路抑制剂的每日用量可以在1－1000mg/kg，优选5－500mg/kg，更优选10－200mg/kg，最优选20－150mg/kg，所述的用量以化合物(I)的形式计量。
所述的EGFR阳性(或过度表达)的癌症，可以是多种实体瘤，例如肺癌、乳腺癌，优选非小细胞肺癌。在本发明特别优选的实施方案中，所述的癌症是对EGFR抑制剂产生耐药的癌症，特别是肺癌，如非小细胞肺癌。其中所述的EGFR抑制剂包括吉非替尼、厄洛替尼、阿法替尼、埃克替尼等，优选厄洛替尼。
在本发明列为优选的实施方案中，所述的Hedgehog信号通路抑制剂与EGFR抑制剂联合使用，优选所述的抑制剂选自吉非替尼、厄洛替尼、阿法替尼和埃克替尼中的一种或多种，优选厄洛替尼。本发明中，联合使用指是是两种或多种药物在同一给药周期内都施予给药对象，但二者是否同时施用则不受限制，可以有先有后，可以有一定的时间间隔。本发明的EGFR抑制剂的用量可以在每日1－1000mg/kg，优选5－500mg/kg，更优选10－200mg/kg，最优选20－150mg/kg。
本发明中的EGFR抑制剂可以是可药用盐的形式存在，如各种无机酸或有机酸盐，优选盐酸盐。
式(I)化合物和前述的EGFR抑制剂或它们的药学上可接受的盐也可以与药学上可接受的载体一起制成本领域熟知的组合物形式，如片剂、胶囊、颗粒剂、注射剂等。本发明还涉及含有选自式(I)化合物和EGFR抑制剂或者它们的药学上可接受的盐的组合物在制备治疗前述胰腺癌的药物中的用途。
附图说明
图1显示厄洛替尼单用或与式(I)化合物合用对人肺癌NCI-H292裸小鼠移植瘤的疗效。Erl表示厄洛替尼，HR表示化合物(I)，Erl→溶剂：指荷瘤小鼠先用厄洛替尼治疗17天，然后改用溶剂再处理14天；其它依次类推。TGI：肿瘤生长抑制率(tumor growthinhibition)。
图2显示厄洛替尼单用或与式(I)化合物合用对荷瘤裸小鼠体重的影响。Erl表示厄洛替尼，HR表示化合物(I)，Erl→溶剂：指荷瘤小鼠先用厄洛替尼治疗17天，然后改用溶剂再处理14天；其它依次类推。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例1：在厄洛替尼体内诱导产生抗药的EGFR高表达的人肺癌NCI-H292模型上，评价Hedgehog抑制剂化合物(I)对厄洛替尼的增效作用
1受试药物
受试化合物(I)参照CN103261198A公开的内容合成。配制方法：化合物(I)用含0.2％Tween 80+0.5％CMC配制；厄洛替尼(盐酸厄洛替尼)用含0.2％Tween80蒸馏水配制。
2实验动物
BALB/cA-nude裸小鼠，6-7周，♀，购自上海斯莱克实验动物有限责任公司。合格证号：SCXK(沪)2007－0005。饲养环境：SPF级。
3实验步骤
裸小鼠皮下接种人肺癌NCI-H292细胞，待肿瘤生长至100-250mm3后，将动物随机分组(D0)。给药剂量和给药方案见表1。每周测2－3次瘤体积，称鼠重，记录数据。肿瘤体积(V)计算公式为：
V＝1/2×a×b2其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100其中T、C为实验结束时的肿瘤体积；T0、C0为实验开始时的肿瘤体积。
4结果
人肺癌NCI-H292高表达EGFR,是研究EGFR抑制剂疗效的敏感模型，但长期应用EGFR抑制剂后，NCI-H292产生抗药，表现为EGFR抑制剂如厄洛替尼疗效降低。本次试验分二阶段，第一阶段NCI-H292体内肿瘤模型先用厄洛替尼治疗17天，诱导NCI-H292产生抗药性，从图1可见，厄洛替尼治疗7天后，肿瘤开始产生抗药性，至17天时，抗药性开始增加(但此时抑瘤率仍高达72.2％)；然后试验进入第二阶段，把厄洛替尼处理后产生抗药性的NCI-H292肿瘤分为4组(见表1和图1)，分别给予不同的处理。从表1和图1可见，厄洛替尼停药后，肿瘤快速生长；继续应用厄洛替尼，疗效明显下降，抑瘤率从72.2％下降到29.4％，说明明显的抗药；改用Hedgehog抑制剂化合物(I)，并不能产生明显的疗效；但继续应用厄洛替尼，同时加用化合物(I)，则产生明显的协同抗肿瘤作用，给药早期大部分肿瘤均产生消退，至试验结束时，仍有2/6小鼠肿瘤部分消退；厄洛替尼与化合物(I)合用，毒性并没有明显增加，荷瘤小鼠仍能较好的耐受。
表1.厄洛替尼单用或与化合物(I)合用对人肺癌NCI-H292裸小鼠移植瘤的疗效
D0:第一次给药时间；P valuea:指与溶剂相比；P valueb:指与Erl→溶剂相比；Student’s t检验。Erl指厄洛替尼；HR指化合物(I)；Erl→溶剂:指荷瘤小鼠先用厄洛替尼治疗17天，然后改用溶剂再处理14天；其它依次类推。
5结论
肺癌NCI-H292经厄洛替尼治疗后，产生抗药性；厄洛替尼停药后，肿瘤恢复快速生长；继续应用厄洛替尼，疗效明显下降；改用Hedgehog抑制剂化合物(I)，并不能产生明显的疗效；但继续应用厄洛替尼，同时加用化合物(I)，则产生明显的协同抗肿瘤作用，且毒性并没有明显增加。
Claims (4)
1.式(I)所示化合物或其可药用盐联合厄洛替尼在制备治疗对厄洛替尼耐药且EGFR过度表达的非小细胞肺癌药物中的用途，
其中，所述式(I)化合物的每日用量为20－150mg/kg，厄洛替尼的每日用量为20－150mg/kg。
2.根据权利要求1所述的用途，其中所述的厄洛替尼为盐酸盐形式。
3.一种治疗对厄洛替尼耐药且EGFR过度表达的非小细胞肺癌的药物组合物，含有如权利要求1中所述的式(I)化合物和厄洛替尼或者它们的药学上可接受的盐，以及药学上可接受的载体，其中所述式(I)化合物的每日用量为20－150mg/kg，所述厄洛替尼的每日用量为20－150mg/kg。
4.权利要求3所述的药物组合物在制备治疗对厄洛替尼耐药且EGFR过度表达的非小细胞肺癌药物中的用途。
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| CN201610116972 | 2016-03-01 |
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