CN108542906A - 治疗增生性疾病的方法 - Google Patents

治疗增生性疾病的方法 Download PDF

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CN108542906A
CN108542906A CN201810135736.8A CN201810135736A CN108542906A CN 108542906 A CN108542906 A CN 108542906A CN 201810135736 A CN201810135736 A CN 201810135736A CN 108542906 A CN108542906 A CN 108542906A
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proliferative disease
braf
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braf inhibitor
cancer
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D·斯图尔特
M·D·塔库尔
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Novartis AG
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

本发明涉及用丝氨酸/苏氨酸激酶抑制剂治疗患者的方法，其中通过间歇给药方案给予丝氨酸/苏氨酸激酶抑制剂来抑制对丝氨酸/苏氨酸激酶抑制剂治疗的抗性。

Description

治疗增生性疾病的方法
本申请为国际申请PCT/US2012/064269进入中国国家阶段的中国专利申请(申请号为201280054663.0，申请日为2012年11月9日，发明名称为“治疗增生性疾病的方法”)的分案申请。
发明内容
本发明涉及抑制对BRAF抑制剂治疗抗性的方法。
发明背景
已熟知激酶参与增生性疾病。例如，肿瘤发生相关激酶包括受体酪氨酸激酶和丝氨酸/苏氨酸激酶、Raf激酶。这些激酶在影响和调节许多细胞功能，如增殖、分化和存活，的信号转导通路中起关键作用。
开发治疗增生性疾病的疗法仍是一项艰巨挑战。不断需要改善的治疗方法，特别是考虑到癌细胞在其生长和存活基本机制、其对治疗剂的应答、以及其突变并变得对所述试剂有耐性或抗性的能力方面而言的许多变化。
Raf激酶是促分裂原活化蛋白激酶(MAPK)信号通路的一部分，包括Ras-Raf-MEK1-ERK信号分子。Raf具有三个不同的同种型，即A-Raf、B-Raf和C-Raf，由其与上游调节因子Ras相互作用的能力来区分。Ras基因之一的激活突变可在约20％的所有肿瘤中观察到，且Ras/Raf/MEK/ERK通路在约30％的所有肿瘤中被激活(Bos等，Cancer Res.49:4682-4689,1989；Hoshino等，Oncogene 18:813-822，1999)。B-Raf激酶结构域中的激活突变发生于约66％黑素瘤、12％结肠癌和14％肝癌中(Davies等,Nature417:949-954,2002；Yuen等,Cancer Research 62:6451-6455,2002；Brose等,Cancer Research 62:6997-7000,2002)。
小分子RAF抑制剂，如威罗菲尼，已证实了以下概念验证(proof-of-concept)：BRAFV600E是黑素瘤增殖和生存的关键驱动因子，如晚期临床试验中患者的肿瘤消退和生存延长所证明。不幸的是，当迅速发展出RAF抑制剂抗性时，所述肿瘤反应短暂。
附图说明
图1.连续和间歇给药式II的BRAF抑制剂的比较，显示通过间歇给药对耐药细胞的生长优势的去除延迟或防止对BRAF抑制剂的抗性的发生。
发明详述
本发明基于以下发现：Raf激酶耐受肿瘤细胞‘适应性低于’Raf激酶抑制剂敏感性肿瘤细胞且在没有Raf激酶抑制剂情况下相比敏感细胞有选择劣势。因此，根据本发明，以间歇给药方案给予Raf激酶抑制剂可抑制对Raf激酶抑制剂治疗的抗性。
抑制对治疗的抗性指延迟或防止对Raf激酶抑制剂治疗抗性的发生。
本申请中，间歇给药方案指B-Raf激酶抑制剂进行一段时间给药，随后的一段时间暂停用B-Raf激酶抑制剂治疗。例如，Raf激酶抑制剂持续4周每天给药，之后的2周不治疗，并且在患者使用Raf激酶抑制剂治疗期间重复该循环。
BRAF抑制剂和其在治疗增生性疾病中的应用是本领域已知的。
威罗菲尼(PLX4032)是FDA批准用于治疗黑素瘤患者的BRAF抑制剂，所述患者的肿瘤表达BRAF V600E突变。威罗菲尼具有以下化学结构：
抑制MAPK通路中特定激酶的另一类化合物是苯并咪唑基吡啶基醚。美国专利7,482,367公开了式I的B-RAF激酶抑制剂，所述专利通过引用全文纳入本文。
抑制MAPK通路中特定激酶的另一类化合物是吡唑嘧啶。WO2011/025927通过引用全文纳入本文，其公开了作为BRAF激酶，尤其是带有BRAFV600E突变的BRAF激酶，的抑制剂的式II化合物：
本方法中，所述BRAF抑制剂优选是式II的化合物。
在设计用于测量BRAF抑制剂抗性出现的早期传代原发性人黑素瘤移植瘤模型中，我们确定了用BRAF抑制剂以临床相关剂量通过长期连续给药方案治疗移植瘤导致耐药性肿瘤在4-6周过程中出现。个体肿瘤内的药效动力学(PD)分析表明，RAF-MEK-ERK通路在耐药性肿瘤中仍受抑制，尽管抑制程度和持续时间小于敏感性肿瘤。此外，通路抑制和恢复的动力学在各耐药性肿瘤间有所不同。生化分析表明丝氨酸/苏氨酸激酶和丝氨酸/苏氨酸激酶负反馈环的调节可能参与耐药性、以及BRAF V600E表达上调。肿瘤应答的药理评价为肿瘤细胞群和耐药性进化提供见解。增加给予荷耐药性瘤小鼠的药物剂量导致显著但短暂的肿瘤反应，然后是肿瘤发展。综合PD数据，可以得出合理的结论，即存在大量肿瘤细胞异质性，且肿瘤能迅速适应因给药而施加的选择压力。通过中止对移植有耐药性小鼠的治疗得到了支持该结论的进一步证据。停药后，肿瘤起初在数天到数周内消退，之后再生长。这些数据表明，在处于选择压力下的肿瘤细胞群内出现的适应性使得所述细胞较为不适应药物缺乏的情况。
所有耐药性肿瘤在BRAF抑制剂化合物存在情况下具有的p-ERK水平高于敏感性肿瘤且给药后的恢复速率更快。耐药性肿瘤之间的恢复动力学可变。BRAF耐药性肿瘤取决于用于生长的药物存在和导致肿瘤消退的药物移除。缺乏化合物时，耐药细胞的适应性低于敏感细胞。本发明利用此发现以通过间歇给药方案给予BRAF抑制剂来抑制对BRAF抑制剂治疗的抗性。
因此，本发明包括治疗增生性疾病的方法，所述方法包括通过间歇给药方案给予BRAF激酶抑制剂来抑制对BRAF激酶抑制剂治疗的抗性。
本发明特定包括治疗其特征在于BRAF激酶突变的增生性疾病的方法，所述方法包括通过间歇给药方案给予式II的BRAF抑制剂来抑制对式II的BRAF抑制剂治疗的抗性。
在一个优选实施方式中，本发明还涉及治疗特征为BRAF激酶突变的增生性疾病的方法，所述方法包括通过间歇给药方案给予BRAF抑制剂来抑制对BRAF抑制剂治疗的抗性。
本发明的此方面还涉及一种方法，其中BRAF突变是V600突变，如BRAFV600E。
由本发明方法治疗的增生性疾病包括癌症，例如但不限于，膀胱癌、乳腺癌、脑癌、头颈癌、肝癌、胆道癌、癌、急性和慢性淋巴细胞白血病、急性和慢性髓细胞性白血病、慢性骨髓单核细胞性白血病、结直肠癌、胃癌、胃肠道间质瘤、胶质瘤、淋巴瘤、黑素瘤、多发性骨髓瘤、骨髓及外骨髓增生性疾病、神经内分泌癌、肺癌、胰腺癌、卵巢癌、前列腺癌、肾细胞癌、肉瘤和甲状腺癌，如甲状腺乳头状癌。其他增生性疾病包括肥大细胞白血病、生殖细胞瘤、小细胞肺癌、胃肠道间质瘤、成神经细胞瘤和骨肉瘤。
更特定地，由本发明方法治疗的增生性疾病是特征为V600突变如BRAFV600E，的黑素瘤，或特征为V600突变如BRAFV600E的结直肠癌。
在一个重要的方面，所述间歇给药方案包括给予BRAF抑制剂持续4周，之后的2周时间不治疗，并在患者用BRAF抑制剂治疗时或者直到出现耐药性时重复所述循环。然而，其它间歇给药方案包括，例如，1周给药1周停药，2周给药1或2周停药，3周给药1、2或3周停药，4周给药1、2、3或4周停药，特别是4周给药1周停药或4周给药2周停药，5周给药1、2、3、4、或5周停药，6周给药1、2、3、4、5、或6周停药，等循环。
本发明还包括BRAF抑制剂在制备用于治疗增生性疾病的药物中的用途，其中所述BRAF抑制剂以间歇给药方案给予。特别地，式II的BRAF抑制剂用于制备治疗增生性疾病的药物，其中式II的BRAF抑制剂以间歇给药方案给予。
以下实施例描述本发明。
实施例1
将第3代Hmex1906原发性人黑素瘤植入裸鼠。监控小鼠，直到植入的肿瘤达到200-400mm3。一旦达到该尺寸，向小鼠一天两次给药5mg/kg Raf抑制剂(式II的化合物)，持续4周。一些小鼠继续治疗，而另一些接受4周治疗2周停药的间歇治疗方案。
结果示于图1。所有连续接受式II化合物的小鼠均出现耐药性，但没有证据显示接受间歇给药方案的小鼠出现耐药性。

Claims (5)

1.一种治疗特征为BRAF激酶突变的增生性疾病的方法，所述方法包括通过间歇给药方案给予式II的BRAF抑制剂来抑制对式II的BRAF抑制剂治疗的抗性
2.如权利要求1所述的方法，其中所述BRAF突变是V600突变。
3.如权利要求1所述的方法，其中所述增生性疾病是特征为V600突变的黑素瘤，或特征为V600突变的结直肠癌。
4.如权利要求1所述的方法，其特征在于，所述增生性疾病是特征为BRAFV600E的黑素瘤，或特征为BRAFV600E的结直肠癌。
5.式II的BRAF抑制剂
在制备用于治疗增生性疾病的药物中的用途，其中所述BRAF抑制剂以间歇给药方案给予。
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