CN115997122A - 类维生素a与癌治疗剂的组合疗法有效的癌患者的选择方法、及类维生素a与癌治疗剂的组合药物 - Google Patents
类维生素a与癌治疗剂的组合疗法有效的癌患者的选择方法、及类维生素a与癌治疗剂的组合药物 Download PDFInfo
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Abstract
本发明提供一种类维生素A与癌治疗剂的组合疗法有效的癌患者的选择方法,该方法包括选择患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者的步骤。此外,本发明还提供一种药物,其以患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者为对象,并且将类维生素A与癌治疗剂组合来给药。
Description
技术领域
本发明涉及一种类维生素A(retinoid)与癌治疗剂的组合疗法有效的癌患者的选择方法、及对所选择的癌患者有效的类维生素A与癌治疗剂的组合药物。
背景技术
间质(Stroma)是构成癌微环境的癌相关纤维原细胞、细胞外基质、免疫细胞、血管等的统称。胰腺癌(也称为“胰腺肿瘤”)、胆管癌、乳腺癌、肺癌等一些恶性肿瘤中含有大量间质,这被认为是抗癌药(anticancer drug)的抗性(resistance)的原因。作为间质的主要组成部分的癌相关纤维原细胞(Cancer-associated fibroblast)通过各种机制促进癌细胞的生长,并且源自癌相关纤维原细胞的丰富的细胞外基质阻碍抗癌药的渗透。因此,癌相关纤维原细胞被认为是促癌因子(cancer-promoting factor)。基于上述内容,尝试了以癌相关纤维原细胞为靶标的癌治疗,但是与预期相反,产生了具有高度恶性的癌细胞(非专利文献1)。
另一方面,最近的研究显示,除了上述促癌性癌相关纤维原细胞以外,还存在肿瘤抑制性癌相关纤维原细胞,并且作为其特异性分子标志物(molec ular marker),鉴定出GPI锚定型(GPI-anchored)膜分子即meflin(非专利文献2~4)。此外,随着癌的发展,肿瘤抑制性癌相关纤维原细胞能够变化(性质转换)为肿瘤促进性癌相关纤维原细胞,然而,通过特定的药剂,肿瘤促进性癌相关纤维原细胞也能够恢复(重新编程)到肿瘤抑制性癌相关纤维原细胞。目前,作为将肿瘤促进性癌相关纤维原细胞重新编程为肿瘤抑制性癌相关纤维原细胞的药剂,已知有ATRA(all-trans retinoic acid:全反式维A酸)或维生素D(非专利文献5~9)。
如果能够开发一种针对患有具有大量抗癌药抵抗性间质(anticancer dr ug-resistant stroma)的恶性肿瘤的一些癌患者的特异性高的治疗法,而且如果能够开发一种能够准确地选择该治疗法有效的一些癌患者的方法,认为能够降低对癌患者进行无效治疗的可能性,有助于降低医疗费,并且还有助于通过最佳治疗改善患者的预后。
现有技术文献
非专利文献
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发明内容
本发明要解决的技术问题
本发明的目的在于提供一种对患有具有大量抗癌药抵抗性间质的恶性肿瘤的癌患者进行治疗的高疗效药物、及提供一种使用该药物的治疗有效的癌患者的选择方法。
解决技术问题的技术手段
为了解决上述课题,本发明包括下述发明。
(1)一种类维生素A与癌治疗剂的组合疗法有效的癌患者的选择方法,该方法包括选择患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者的步骤。
(2)根据(1)所述的方法,其中,
所述选择癌患者的步骤包括在从受检癌患者得到的恶性肿瘤组织中检测至少1个癌相关纤维原细胞。
(3)根据(1)或(2)所述的方法,其中,
所述选择癌患者的步骤包括制备从受检癌患者得到的恶性肿瘤组织的病理组织标本,在显微镜观察下检测至少1个癌相关纤维原细胞。
(4)根据(1)至(3)中任一项所述的方法,其中,
所述选择癌患者的步骤包括在显微镜下观察从受检癌患者得到的恶性肿瘤组织的病理组织标本,在包含癌细胞区域和间质区域的任意高倍放大视野(high-magnification field)中检测至少1个癌相关纤维原细胞。
(5)根据(3)或(4)所述的方法,其中,
癌相关纤维原细胞的检测是通过显微镜观察经苏木精-伊红染色的病理组织标本来进行。
(6)根据(3)或(4)所述的方法,其中,
癌相关纤维原细胞的检测是通过对癌相关纤维原细胞的标志物分子(mar kermolecule)的免疫组织化学染色(immunohistochemical staining)或原位杂交(in situhybridization)来进行。
(7)一种药物,其以通过(1)至(6)中任一项所述的方法选择的癌患者为对象,并且将类维生素A与癌治疗剂组合来给药。
(8)根据(7)所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
(9)根据(7)或(8)所述的药物,其中,
所述类维生素A为他米巴罗汀(tamibarotene)。
(10)根据(7)至(9)中任一项所述的药物,其中,
所述类维生素A以预先给药的方式使用。
(11)一种用于增强癌治疗剂的作用及/或用于促进对靶向肿瘤组织的癌治疗剂递送的药物,其以通过(1)至(6)中任一项所述的方法选择的癌患者为对象,并且以类维生素A为有效成分。
(12)根据(11)所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
(13)根据(11)或(12)所述的药物,其中,
所述类维生素A为他米巴罗汀。
(14)一种用于增强癌治疗剂的作用的药物,其以通过(1)至(6)中任一项所述的方法选择的癌患者为对象,并且以使得在肿瘤组织细胞中过度表达me flin的组合物为有效成分。
(15)根据(14)所述的药物,其中,
所述使得过度表达meflin的组合物为含有meflin基因的病毒载体。
(16)根据(14)或(15)所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
(17)一种药物,其以通过所述(1)至(6)中任一项所述的方法选择的癌患者为对象,并且将诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与癌治疗剂组合来给药。
(18)根据(17)所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
(19)根据(17)或(18)所述的药物,其中,
预先使用诱导癌间质中的赖氨酰氧化酶活性抑制的药剂。
(20)一种用于增强癌治疗剂的作用及/或用于促进对靶向肿瘤组织的癌治疗剂递送的药物,其以通过所述(1)至(6)中任一项所述的方法选择的癌患者为对象,并且以诱导癌间质中的赖氨酰氧化酶活性抑制的药剂为有效成分。
(21)根据(20)所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
发明效果
根据本发明,能够提供一种对患有具有大量抗癌药抵抗性间质的恶性肿瘤的癌患者进行治疗的高疗效药物。此外,本发明能够提供一种使用所述药物的治疗有效的癌患者的选择方法。根据本发明,能够确定治疗疗效高的癌患者,并且仅选择能够进行治疗的癌患者,因此能够避免治疗效果差的癌患者支付高额的医疗费来进行不必要的治疗。
附图说明
图1中示出通过手术得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(未分化癌(anaplastic cancer))的苏木精-伊红(HE)染色标本的观察结果。
图2中示出通过手术得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺导管内乳头状粘液腺瘤(intrapancreatic papillary mucin ous adenoma))的HE染色标本的观察结果。
图3中示出通过手术得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(管状腺癌(tubular adenocarcinoma))的HE染色标本的观察结果。
图4中示出通过手术得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(管状腺癌)的HE染色标本的观察结果。
图5中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(腺泡细胞癌(acinar cell carcinoma))的HE染色标本的观察结果。
图6中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(腺泡细胞癌)的HE染色标本的观察结果。
图7中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺导管内乳头状粘膜腺癌((intrapancreatic papillary mucosaladenocarcinoma)(非侵袭性癌(non-invasive cancer)))的HE染色标本的观察结果。
图8中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺导管内乳头状粘液腺瘤(IPMA))的HE染色标本的观察结果。
图9中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(粘液囊肿肿瘤(mucous cyst tumor))的HE染色标本的观察结果。
图10中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(神经内分泌肿瘤(G1、胰岛素瘤))的HE染色标本的观察结果。
图11中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(神经内分泌肿瘤(G1、gastrinoma:胃泌素瘤))的HE染色标本的观察结果。
图12中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺上皮内瘤变(pancreatic intraepithelial neoplastic lesion:PanIN))的HE染色标本的观察结果。
图13中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(浆液性囊腺瘤(serous cystadenoma))的HE染色标本的观察结果。
图14中示出通过手术得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(实性假乳头状肿瘤((solid pseudopapillary neoplasm:SPN))的HE染色标本的观察结果。
图15中示出通过胰腺肿瘤活检(biopsy)得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(管状腺癌)的HE染色标本的观察结果。
图16中示出通过胰腺肿瘤活检得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(未分化癌)的HE染色标本的观察结果。
图17中示出通过胰腺肿瘤活检得到的、在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺导管内乳头状粘膜腺癌(侵袭性癌(invasive canc er)))的HE染色标本的观察结果。
图18中示出通过胰腺肿瘤活检得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(腺泡细胞癌)的HE染色标本的观察结果。
图19中示出通过胰腺肿瘤活检得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(实性假乳头状肿瘤(SPN))的HE染色标本的观察结果。
图20中示出通过胰腺肿瘤活检得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(神经内分泌肿瘤)的HE染色标本的观察结果。
图21中示出通过胰腺肿瘤活检得到的、在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤(胰腺导管内乳头状粘液腺瘤(IPMA))的HE染色标本的观察结果。
图22中示出对在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤的组织标本,使用抗meflin抗体进行免疫组织染色(左)及使用与meflin基因的mRNA杂交的探针进行原位杂交(ISH)的结果。
图23中示出对在间质中产生癌相关纤维原细胞的浸润的胰腺肿瘤的组织标本,使用抗meflin抗体进行免疫组织染色(左)及使用与meflin基因的mRNA杂交的探针进行原位杂交(ISH)的结果。
图24中示出对在间质中未产生癌相关纤维原细胞的浸润的胰腺肿瘤的组织标本,使用抗meflin抗体进行免疫组织染色(左)及使用与meflin基因的mRNA杂交的探针进行原位杂交(ISH)的结果。
图25中示出实施例3的方案。
图26中示出移植15天后的肿瘤体积的测量结果,其中,(A)表示单独移植人胰腺癌细胞的裸小鼠中的吉西他滨(gemcitabine)和他米巴罗汀给药组(Gem+AM80组)及吉西他滨和DMSO给药组(Gem+DMSO组)的结果、(B)表示同时移植人胰腺癌细胞和人胰腺星形胶质细胞(human pancreatic astr ocyte)的裸小鼠中的Gem+AM80组和Gem+DMSO组的结果。
图27中示出将原代小鼠间充质干细胞培养至100%融合,并将ATRA、AM80或AM580添加到培养基之后经过48小时后的基因表达的测量结果,其中,(A)是meflin基因(Islr)、(B)是肌动蛋白基因(Acta2)、(C)是I型胶原蛋白基因(Col1a1)、(D)是III型胶原蛋白基因(Col3a1)的结果。
图28中示出实施例6的方案。
图29中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例6中,对各组的移植后的经时肿瘤体积进行测量的结果。
图30中示出在移植22天后摘除肿瘤并制备组织切片的实施例6中,对肿瘤中的meflin基因(Islr)表达进行原位杂交(ISH)检测的结果,其中,(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较这两组之间的每个高倍放大视野的Islr阳性信号点数的图。
图31中示出在移植22天后摘除肿瘤并制备组织切片的实施例6中,对肿瘤中的肌动蛋白基因(Acta2)表达进行原位杂交(ISH)检测的结果,其中,(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较这两组之间的每个高倍放大视野的Islr阳性信号点数的图。
图32中示出在移植22天后摘除肿瘤并制备组织切片,且用抗CD31抗体进行免疫染色的实施例6中,对血管腔面积进行测量的结果,其中,(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较这两组之间的血管腔面积的图。
图33中示出实施例7的方案。
图34中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例6中,对各组的移植后的经时肿瘤体积进行测量的结果。
图35中示出实施例8的方案。
图36中示出在使用了皮下移植小鼠胰腺癌细胞的裸小鼠的实施例8中,对各组的移植后的经时肿瘤体积进行测量的结果。
图37中示出实施例9的方案。
图38中示出在使用了小鼠自发性胰腺癌发病模型(spontaneous pancre aticcancer onset model)(KPC小鼠)的实施例9中,对分成各组后的经时肿瘤体积进行测量的结果。
图39中示出实施例11的方案。
图40中示出在使用了meflin缺陷型小鼠的实施例11中,对各组的移植后的经时肿瘤体积进行测量的结果。
图41中示出在移植24天后摘出肿瘤并制备组织切片的实施例11中,对肿瘤中的肌动蛋白基因(Acta2)表达进行原位杂交(ISH)检测的结果,其中,(A)是吉西他滨给药组(Gem组)的代表性显微图像、(B)是吉西他滨和他米巴罗汀给药组(Gem+AM80组)的代表性显微图像、(C)是比较这两组之间的每个高倍放大视野的Acta2阳性信号点数的图。
图42中示出实施例12的方案。
图43中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例12中,在对瘤内分别给药使得在感染细胞中过度表达Meflin的仙台病毒(SeV-Meflin)及使得在感染细胞中过度表达GFP的仙台病毒(SeV-GFP),并且在移植17天后摘除肿瘤并制备组织切片的情况下,对肿瘤中的meflin基因(Islr)表达进行原位杂交(ISH)检测的结果,其中,(A)是SeV-GFP给药组的代表性显微图像,(B)是SeV-Meflin给药组的代表性显微图像。
图44中示出表示在实施例12中,比较这两组的移植17天后的肿瘤体积的图。
图45中示出实施例13的方案。
图46中示出表示在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例13中,将瘤内给药SeV-Meflin之后接着给药吉西他滨的组及对瘤内给药SeV-GFP之后接着给药吉西他滨的组的、移植17天后的肿瘤体积进行比较的图。
图47中示出通过将稳定地表达小鼠meflin的细胞的培养上清液和对照细胞的培养上清液分别与重组人赖氨酰氧化酶L2(LoxL2)进行混合来对人赖氨酰氧化酶活性进行测量的结果。
图48中示出利用二次谐波显微镜对野生型小鼠自发性胰腺癌发病模型(KPC小鼠)及meflin缺陷型KPC小鼠的胰腺肿瘤间质中的胶原蛋白的排列(collagen arrangement)进行测量的结果,(A)是野生型KPC组的代表性二次谐波显微图像、(B)是meflin缺陷型KPC组的代表性二次谐波显微图像、(C)比较这两组之间的胶原蛋白曲率(curvature)(线性)的图。
图49中示出皮下移植小鼠胰腺癌细胞的小鼠给药他米巴罗汀或溶剂(DMSO),并利用二次谐波显微镜对肿瘤间质中的胶原蛋白的排列进行测定的结果,其中,(A)是对照组的代表性二次谐波显微图像、(B)是他米巴罗汀给药组的代表性二次谐波显微图像、(C)是比较这两组之间的胶原蛋白的曲率(线性)的图。
图50中示出实施例17的方案。
图51中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例17中,对预先给药他米巴罗汀之后给药吉西他滨的组、预先给药他米巴罗汀之后共同给药(co-administered)他米巴罗汀和吉西他滨的组、及代替他米巴罗汀给药DMSO和吉西他滨的组的移植后的经时肿瘤体积进行测量的结果。
图52中示出实施例18的方案。
图53中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例18中,对抗PD-L1抗体给药组、及抗PD-L1抗体和他米巴罗汀给药组的移植后的经时肿瘤体积进行测量的结果。
图54中示出在实施例18中,直到两组中的所有小鼠死亡为止的存活率变化趋势。
图55中示出实施例19的方案。
图56中示出在使用了皮下移植小鼠胰腺癌细胞的小鼠的实施例19中,对抗PD-L1抗体给药组、抗PD-L1抗体和他米巴罗汀给药组、及给药IgG的对照组的移植后的经时肿瘤体积进行测量的结果。
图57中示出在实施例19中,直至所有组的所有小鼠死亡为止的存活率变化趋势。
图58中示出实施例20的方案。
图59中示出在使用了皮下移植小鼠膀胱癌细胞的小鼠的实施例20中,对抗PD-L1抗体给药组、及抗PD-L1抗体和他米巴罗汀给药组的移植后的经时肿瘤体积进行测量的结果。
图60中示出在使用了皮下移植小鼠肺癌细胞的小鼠的实施例19中,对抗PD-L1抗体给药组、及抗PD-L1抗体和他米巴罗汀给药组的移植后的经时肿瘤体积进行测量的结果。
图61中示出实施例23的方案。
图62中示出在使用了皮下移植小鼠胰腺癌细胞的meflin缺陷型小鼠的实施例23中,对抗PD-L1抗体给药组、抗PD-L1抗体和他米巴罗汀给药组、及给药IgG的对照组的移植后的经时肿瘤体积进行测量的结果。
图63中示出在实施例23中,直至所有组的所有小鼠死亡为止的存活率变化趋势。
图64中示出在使用了皮下移植小鼠胃癌细胞的小鼠的实施例24中,对抗PD1抗体给药组、及抗PD1抗体和他米巴罗汀给药组的移植后的经时肿瘤体积进行测量的结果。
具体实施方式
〔类维生素A与癌治疗剂的组合药物〕
本发明提供一种将类维生素A与癌治疗剂组合来给药的治疗癌的药物(以下,记载为“本发明的第1药物”)。本发明的第1药物的给药对象是患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者。患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者能够通过以下所述的方法进行选择。本发明还包括一种类维生素A与癌治疗剂的组合疗法有效的癌患者的选择方法。
类维生素A与癌治疗剂的组合疗法有效的癌患者的选择方法(以下,记载为“本发明的癌患者选择方法”)包括选择患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者的步骤。该癌患者的选择步骤可以包括在从受检癌患者得到的恶性肿瘤组织中检测至少1个癌相关纤维原细胞(以下有时缩写成“CAF”)。恶性肿瘤组织只要是从受检癌患者得到的恶性肿瘤组织,则可以通过活检或手术来获得。利用从受检癌患者得到的恶性肿瘤组织,可以制备病理组织标本,也可以制备细胞悬浮液,还可以制备细胞破碎溶液(celldisruption liquid)。检测CAF方法并没有特别限定,可以是检测CAF特异性核酸的方法、检测CAF特异性蛋白质的方法、或检测CAF特异性形态(specific morphology)的方法。
在本发明的癌患者选择方法中,选择患有在间质中产生CAF的浸润的恶性肿瘤的癌患者的步骤可以包括制备从受检癌患者得到的恶性肿瘤组织的病理组织标本,在显微镜观察下检测至少1个CAF。病理组织标本的制备方法并没有特别限定,能够根据所使用的染色方法或检测方法,从公知的方法中适当选择。显微镜观察可以在病理组织标本的整个区域进行,当在显微镜观察中检测出至少1个CAF的情况下,则能够将该受检患者视为本发明的第1药物的给药有效的癌患者。在制备了多个病理组织标本时,当在任一个病理组织标本中检测出至少1个CAF的情况下,能够将该接受检查患者视为本发明的第1药物的给药有效的癌患者。
在本发明的癌患者选择方法中,选择患有在间质中产生CAF的浸润的恶性肿瘤的癌患者的步骤可以包括在显微镜下观察从受检癌患者得到的恶性肿瘤组织的病理组织标本,在包含癌细胞区域和间隙区域的任意的高倍放大视野中检测1个以上的CAF。1个高倍放大视野中的CAF的个数为至少1个即可,也可以为2个、3个、4个、5个、6个、7个、8个、9个、或10个以上。显微镜观察下的“高倍放大视野”是指,使用40倍的物镜和10倍的目镜以400倍进行观察,也称为高倍视野(high power field;HPF)。
CAF能够通过对病理组织标本进行苏木精-伊红(Hematoxylin Eosin)染色(以下,有时缩写成“HE染色”)来进行检测。在这种情况下,通常,病理诊断医生会利用显微镜观察HE染色标本,以从形态学上判定CAF的有无。
在本发明的癌患者选择方法中,可以利用通过免疫组织化学(Immunohistochemistry、以下有时缩写成“IHC”)检测CAF的标志物分子的方法,也可以利用通过原位杂交(以下,有时缩写成“ISH”)来检测CAF的标志物分子的方法。当利用IHC进行检测的情况下,能够使用与CAF的标志物分子特异性结合的抗体,根据常规方法制备IHC标本。当通过ISH进行检测的情况下,能够使用与CAF的标志物分子的mRNA特异性杂交(hybridizingspecif ically)的探针,根据常规方法制备ISH标本。
CAF的标志物分子包括:α平滑筋肌动蛋白(αSMA)、meflin、成纤维细胞激活蛋白(fibroblast activation protein:FAP)、血小板衍生生长因子受体α(PDGFRα)、血小板衍生生长因子受体β(PDGFRβ)、成纤维细胞特异蛋白1(fibroblast specific protein 1:FSP1)、平足蛋白(Podoplanin)、骨膜素(periostin)、gremlin、肌间线蛋白(desmin)、CXCL12、波形蛋白(vimentin)、腱生蛋白-C(tenascin-C)、NG2、ASPN、斯钙素-1(STC-1)、Gli1、I型胶原蛋白(Col1a1)等。作为与这些标志物分子特异性结合的抗体能够使用市售的抗体。与这些标志物分子的mRNA特异性杂交的探针,能够基于对这些标志物分子进行编码的基因的碱基序列,通过公知的方法制备。对这些标志物分子进行编码的基因的碱基序列能够从公知的数据库(NCBI等)获取。
本发明的第1药物中所使用的类维生素A的粒子包括:阿利维A酸(acitretinoin)、阿达帕林(adapalene)、AGN194204(也称为IRX4204、NRX194204、VTP 194204)、AGN195183、阿利维A酸(alitretinoin、也称为9-cis-Retinoic acid)、amsilarotene、AM580、贝沙罗汀(bexarotene)、双酚A二缩水甘油醚(Bisphenol A diglycidyl ether、也称为BADGE)、芬维A胺(fenretinide)、4-羟基视黄酸(4-Hydroxyretinoic acid)、异维A酸(isotretinoin、也称为13-cis-Retinoic acid)、LG268、LGD1550、peretinoin、乙酸视黄酯(Retinylacetate)、他米巴罗汀(tamibarotene、也称为AM80)、他扎罗汀(tazarotene)、维A酸(tretinoin、也称为全反式维生素A(ATRA))、TTNPB等。优选他米巴罗汀。在本说明书中,“类维生素A”包括“维生素A衍生物”、“维生素A类似物质”、“维A酸受体(RAR)激动剂”及“维A酸X受体(RXR)激动剂”,但不包括“维A酸受体(RAR)拮抗剂”或“维A酸X受体(RXR)拮抗剂”。
类维生素A可以形成盐,该盐优选为药学上可接受的盐。例如包括:盐酸、硫酸、乳酸、酒石酸、马来酸、富马酸、草酸、苹果酸、柠檬酸、油酸、棕榈酸、硝酸、磷酸、三氟乙酸、甲磺酸、苯磺酸、对甲苯磺酸等的盐;钠、钾、钙等碱金属或者碱土类金属的盐;氢氧化铝或碳酸盐的盐;及三乙胺、苄胺、二乙醇胺、叔丁胺、二环己胺、精氨酸等的盐等。
如在后述的实施例中所示,本发明人等发现,类维生素A通过促进与其并用的癌治疗剂向在间质中产生CAF的浸润的恶性肿瘤的递送,增强癌治疗剂的作用。因此,类维生素A可以说是用于增强与其并用的癌治疗剂的作用的药物的有效成分。此外,类维生素A可以说是促进与其并用的癌治疗剂向靶向肿瘤组织的递送的药物的有效成分。因此,在本发明包括以患有在间质中产生CAF的浸润的恶性肿瘤的癌患者为患者且以类维生素A为有效成分的用于增强癌治疗剂的作用的药物。而且,在本发明包括以患有在间质中产生CAF的浸润的恶性肿瘤的癌患者为患者且以类维生素A为有效成分的促进对靶向肿瘤组织的癌治疗剂递送的药物。
本发明的第1药物中所使用的类维生素A能够根据公知的药物制剂的生产方法((例如,日本药典中描述的方法等),适当配合药学上可接受的载体或添加剂来制剂化。具体而言,药物组合物例如可以是口服制剂或肠胃外制剂,包括:片剂(tablets)(包括:糖衣片、薄膜衣片、舌下片、口腔崩解片、口含片)、丸剂、粉剂、颗粒剂、胶囊(包括软胶囊及微胶囊)、锭剂(troches)、糖浆剂、液剂、乳剂、悬浮剂(suspensions)、控释制剂(例如速释制剂、缓释制剂、缓释微囊等)、气雾剂、膜剂(例如口腔崩解膜、口腔粘膜贴付膜等)、注射剂(例如皮下注射剂、静脉注射剂(intrave nous injection)、肌肉注射剂、腹腔注射剂等)、静脉内输注剂(intrave nous infusion)、经皮吸收制剂、软膏剂、洗剂、贴付剂、栓剂(例如直肠栓剂、阴道栓剂等)、丸剂、鼻用剂、肺用剂(吸入剂)、滴眼剂等。载体或添加剂的量能够根据药物领域中通常使用的范围适当设定。能够添加的载体或添加剂并无特别限定,其例包括:水、生理食盐水、其他水性溶剂、水性或油性载剂(vehicle)等各种载体;赋形剂、粘合剂、pH调节剂、崩解剂、吸收促进剂、润滑剂、着色剂、香料及芳香剂等各种添加剂。
能够与片剂、胶囊等混和的添加剂的例子包括:粘合剂,例如明胶、玉米淀粉、黄芪胶(tragacanth)、阿拉伯树胶;赋形剂,例如结晶性纤维素;溶胀剂(Swelling agents),例如玉米淀粉、明胶、海藻酸等;润滑剂,例如硬脂酸镁;甜味剂,例如蔗糖、乳糖或糖精等;及香料,例如薄荷香料、冬青油和樱桃香料等。当单位剂型为胶囊的情况下,除了上述类型的物质之外,还可以加入例如油、脂等液体载体。用于注射的无菌组合物能够按照通常的制剂化步骤(例如使有效成分溶解或悬浮在注射用水、天然植物油等溶剂中)来制备。作为注射用水性液体,例如可以使用生理食盐水、包含葡萄糖及/或其他辅助物质的等渗溶液(例如D-山梨糖醇、D-甘露糖醇、氯化钠等)等。所述水性液体也可以与例如醇(乙醇等)、多元醇(丙二醇、聚乙二醇等)等适当的助溶剂及非离子性表面活性剂(聚山梨醇酯80、HCO-50等)等组合使用。作为油性液体,例如可以使用芝麻油、大豆油等。所述油性液体也可以与例如苯甲酸苄酯、苯甲醇等助溶剂组合使用。作为能够添加的其他添加剂,例如可举出缓冲剂(例如磷酸盐缓冲液、乙酸钠缓冲液等)、无痛剂(soothing agents)(例如苯扎氯铵、盐酸普鲁卡因等)、稳定剂(例如人血清白蛋白、聚乙二醇等)、防腐剂(例如苯甲醇、苯酚等)、抗氧化剂等。
类维生素A对人或其他哺乳动物(例如,大鼠、小鼠、兔子、羊、猪、牛、猫、狗、猴子等)的毒性低,能够安全给药。制剂中的类维生素A的含量根据剂型、给药方法、载体等而不同,但相对于制剂总量,通常为0.01~100%(w/w)的比例,也可以为0.1~95%(w/w)的比例。
类维生素A的剂量根据给药对象、症状、给药途径等而不同,例如在口服给药的情况下,体重约60kg的人的剂量为约0.01~1000mg/天、优选为约0.1~100mg/天、更优选为约0.5~500mg/天。当肠胃外给药的情况下,单次肠胃外给药的剂量根据患者的状态、症状、给药方法等而不同。例如静脉注射的情况下,剂量例如通常为约0.01~1000mg/kg体重、优选为约0.01~500mg/kg体重、更优选为约0.01~20mg/kg体重。1天的总剂量可以以单剂量或分剂量给药。
本发明的第1药物中所使用的癌治疗剂,并没有特别限定,例如优选为化学治疗剂、免疫治疗剂或激素治疗剂。这些癌治疗剂可以是脂质体制剂。此外,这些癌治疗剂也可以为核酸药物或抗体药物。
化学治疗剂的例子包括:氮芥(nitrogen mustard)、盐酸氮芥-N-氧化物、苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、噻替哌(thiotepa)、卡巴醌(carboquone)、甲苯磺酸英丙舒凡(improsulfan tosylate)、白消安(busulfan)、盐酸尼莫斯汀(nimustine hydrochloride)、二溴甘露醇(mitobronitol),美法仑(melphalan)、达卡巴嗪(dacarbazine)、雷莫司汀(ranimustine)、雌莫司汀磷酸钠(estramustine sodium phosphate)、三亚乙基三聚氰胺(triethylenemelamine)、卡莫斯汀(carmustine)、洛莫斯汀(lomustine)、链脲霉素(streptozocin)、哌泊溴烷(pipobroman)、依托糖苷(etogluside)、卡铂(carboplatin)、顺铂(cisplatin)、米波铂(miboplatin)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、六甲蜜胺(altretamine)、氨莫司汀(ambamustine)、盐酸二溴螺氯铵(dibrospidium)、福莫斯汀(fotemustine)、泼尼莫斯汀(prednimustine)、嘌嘧替派(pumitepa)、苯达莫斯汀(ribomustin)、替莫唑胺(temozolomide)、苏消安(treosulfan)、曲磷胺(trofosfamide)、净司他丁苯马聚合物(zinostatin stimalamer)、adzelesin、半胱胺亚硝脲(cystemustine)、比折来新(bizelesin)等烷化剂;
巯嘌呤(mercaptopurine)、6-巯嘌呤核糖苷(6-mercaptopurine riboside)、硫肌苷(thioinosine)、甲氨蝶呤(methotrexate)、培美曲塞(pemetrexed)、依诺他宾(enocitabine)、阿糖胞苷(cytarabine)、阿糖胞苷烷磷酯(cytarabine ocfosfate)、盐酸安西他滨(ancitabine hydrochloride)、5-FU系薬剂(例如、氟尿嘧啶、替加氟、UFT、去氧氟尿苷、卡莫氟、加洛西他滨、乙嘧替氟(emitefur)、卡培他滨(capecitabine)等)、氨喋呤(aminopterin)、奈拉滨(nelarabine)、亚叶酸钙(leucovorin calcium)、硫鸟嘌呤(Tabloid)、甘氨硫嘌呤(butocin)、亚叶酸钙、左旋亚叶酸钙、克拉屈滨(cladribine)、乙嘧替氟(emitefur)、氟达拉滨(fludarabine)、吉西他滨、羟基脲(hydrocycarbamide)、喷司它汀(pentostatin)、吡曲克辛(piritrexim)、碘苷(idoxuridine)、米托胍腙(mitoguazone)、thiazoplirine、安莫司汀(ambamustine)、苯达莫司汀(bendamustine)等抗代谢药(antimetabolites);
放线菌素D、放线菌素C、丝裂霉素C、色霉素A3、盐酸博莱霉素(bleomycinhydrochloride)、硫酸博莱霉素、硫酸培洛霉素(peplomycin sulfate)、盐酸柔红霉素(daunorubicin hydrochloride)、盐酸多柔比星(doxorubicin hydrochloride)、盐酸阿柔比星(aclarubicin Hydrochloride)、盐酸吡柔比星(pirarubicin hydrochloride)、盐酸表柔比星(epirubicinhydrochloride)、新制癌菌素(neocarzinostatin)、光辉霉素(mithram ycin)、肉瘤霉素(sarkomycin)、嗜癌霉素(carzinophilin)、米托坦(mitotane)、盐酸佐柔比星(zorubicin Hydrochloride)、盐酸米托蒽醌(mitoxantroneHydrochloride)、盐酸伊达比星(idarubicin Hydrochloride)等抗癌抗生素(anticancerantibiotics);及
依托泊苷(etoposide)、磷酸依托泊苷(etoposide)、硫酸长春碱(vinblastine)、硫酸长春新碱(vincristine)、硫酸长春地辛(vindesine)、替尼泊苷(teniposide)、紫杉醇(paclitaxel)、多西他赛(Docetaxel)、长春瑞宾(vinorelbine)、伊立替康(irinotecan)、盐酸伊立替康(irinotecan)等源自植物的抗癌剂等,但并不限定于这些。
分子靶向剂的例子包括:阿法替尼(afatinib)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)、耐昔妥珠单抗(necitumumab)、克唑替尼(crizotinib)、阿莱替尼(alectinib)、拉帕替尼(lapatinib)、曲妥珠单抗(trastuzumab)、曲妥珠单抗恩他新(trastuzumab emtansine)、帕妥珠单抗(pertuzumab)、贝伐珠单抗(bevacizumab)、阿昔替尼(axitinib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、帕唑帕尼(pazopanib)、瑞格非尼(regorafenib)、依维莫司(everolimus)、替西罗莫司(temsirolimus)、西罗莫司(sirolimus)、伊马替尼(imatinib)、达沙替尼(dasatinib)、尼罗替尼(nilotinib)、伯舒替尼(bosutinib)、普纳替尼(ponatinib)、替伊莫单抗(ibritumomab tiuxetan)、奥法木单抗(Ofatumumab)、利妥昔单抗(Rituximab)、维布妥昔单抗(Brentuximab Vedotin)、吉妥珠单抗(gemtuzumabozogamicin)、莫加珠单抗(Mogamulizumab)、阿仑单抗(alemtuzumab)、达雷木单抗(Daratumumab)、奥英妥珠单抗(inotuzumab ozogamicin)、德奴单抗(Denosumab)、硼替佐米(Bortezomib)、乐伐替尼(lenvatinib)、凡德他尼(vandetanib)、色瑞替尼(ceritinib)、依鲁替尼(ibrutinib)、奥希替尼(Osimertinib)、卡非佐米(carfilzomib)、埃洛妥珠单抗(Elotuzumab)、阿西咗脒(ixazomib)、帕博西尼(palbociclib)、奥拉帕尼(olaparib)、阿贝西尼(abemaciclib)、吉列替尼(gilteritinib)、劳拉替尼(lorlatinib)、恩曲替尼(entrectinib)、奎扎替尼(Quizartinib)、达克替尼(dacomitinib)、维奈托克(Venetoclax)、卡博替尼(Cabozantinib)、阿托珠单抗(obinutuzumab)、博纳吐单抗(Blinatumomab)、罗醚酯肽(Romidepsin)、伏立诺他(Vorinostat)、帕诺比诺他(Panobinostat)、恩可菲尼(Encorafenib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、比尼替尼(Binimetinib)、曲美替尼(Trametinib)、托珠单抗(tocilizumab)、司妥昔单抗(siltuximab)、英夫利昔单抗(infliximab)、雷莫芦单抗(ramucirumab)等,但并不限定于这些。
免疫治疗剂的例子包括:必医你舒(picibanil)、克速镇(krestin)、裂裥菌素(schizophyllan)、蘑菰多醣(lentinan)、乌苯美司(ubenimex)、干扰素(interferon)、介白素(interleukin)、巨噬细胞集落刺激因子(macrophage colony stimulating factor)、粒细胞集落刺激因子(granulocyte colony stimulating factor)、红血球生成素(erythropoietin)、淋巴毒素(lymphotoxin)、BCG疫苗(BCG vaccine)、短棒状杆菌(coryneb acterium parvum)、左美素(levamisole)、多糖K(polysaccharide K)、丙考达唑(procodazol)、伊匹单抗(ipilimumab)、曲美单抗(tremelimumab)、纳武单抗(nivolumab)、派立珠单抗(pembrolizumab)、斯巴达珠单抗(spartalizumab)、西米普利单抗(cemiplimab)、阿维鲁单抗(Avelumab)、阿替珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)等,但并不限定于这些。
免疫治疗剂可以为免疫检查点抑制剂。免疫检查点抑制剂的靶分子的例子包括:CTLA-4、PD-1、LAG-3、BTLA、KIR、TIM-3、PD-L1、PD-L2、B7-H3、B7-H4、HVEM、GAL9、CD160、VISTA、BTNL2、TIGIT、PVR、BTN1A1、BTN2A2、BTN3A2、CSF-1R等。免疫检查点抑制剂的靶分子可以为CTLA-4、PD-1或PD-L1。抗CTLA-4抗体包括:伊匹单抗(ipilimumab)、曲美单抗(tremelimumab)等。抗PD-1抗体的例子包括:纳武单抗(nivolumab)、派立珠单抗(pembrolizumab)、斯巴达珠单抗(spartalizumab)、西米普利单抗(cemiplimab)等,作为抗PD-L1抗体,可以举出阿维鲁单抗(Avelumab)、阿替珠单抗(atezolizumab)、德瓦鲁单抗(durvalumab)等。
激素治疗剂的例子包括:磷雌酚(Fosfestrol)、己烯雌酚(diethylstilboestrol)、氯烯雌酚(chlorotrianisene)、乙酸甲羟孕酮(Medroxyprogesterone acetate)、乙酸甲地孕酮(megestrol acetate)、乙酸氯地孕酮(chlormadinone acetate)、乙酸环丙孕酮(cyproterone acetate)、达那唑(danazol)、烯丙基雌烯三醇(allylestrenol)、孕三烯酮(gestrinone)、美帕曲星(mepartricin)、雷洛昔芬(raloxifene)、奥美昔芬(ormeloxifene)、左美洛昔芬(levormeloxifene)、抗雌激素(antiestrogen)(例如柠檬酸泰莫西芬(tamoxifen)、柠檬酸托瑞米芬(toremifene)等)、丸制剂、美雄烷(mepitiostane)、睾内酯(testololactone)、氨格鲁米特(aminoglutethimide)、LH-RH激动剂(例如乙酸戈舍瑞林(goserelin acetate)、布舍瑞林(buserelin)、亮丙瑞林(leuprorelin)等)、屈洛昔芬(droloxifene)、环硫雄醇(epitiostanol)、磺酸乙炔雌二醇(ethinyl estradiol sulfonate)、芳香酶抑制剂(aromatase inhibitors)(例如盐酸法倔唑(fadrozole hydrochloride)、阿那曲唑(anastrozole)、来曲唑(letrozole)、依西美坦(exemestane)、伏氯唑(vorozole)、福美司坦(formestane)等)、抗雄激素(例如氟他胺(flutamide)、比卡鲁胺(bicalutamide)、尼鲁胺(nilutamide)等)、5α-还原酶抑制剂(例如菲那雄胺(finasteride)、依立雄胺(epristeride)等)、肾上腺皮质(suprarenal cortex)激素系药剂(例如地塞米松(dexamethasone)、泼尼松龙(prednisolone)、倍他米松(betamethasone)、曲安西龙(triamcinolone)等)、雄激素合成抑制剂(例如阿比特龙(abiraterone)等)等,但不限于这些。
本发明的第1药物中所使用的类维生素A与癌治疗剂可以以下述方式对给药对象进行给药,即共同给药、或间隔一定时间分别分开来给药。在本说明书中,“组合给药(administered in combination)”是指,类维生素A的适用时期与癌治疗剂的适用时期重叠,并不需要同时给药。在本发明的第1药物中,优选预先开始给药类维生素A,然后经过一段时间再开始给药癌治疗剂。开始给药类维生素A和开始给药癌治疗剂的时间差,并没有特别限定,该时间差可以为1天以上、2天以上、3天以上、4天以上、5天以上、6天以上、7天以上。癌治疗剂的剂量能够按照其临床批准的剂量来确定,并且能够根据给药对象、给药对象的年齢及体重、症状、给药持续时间、剂形、给药方法、药物组合等进行适当选择。
〔包含使得过度表达meflin的组合物作为有效成分的药物〕
本发明提供一种包含使得在肿瘤组织细胞中过度表达meflin的组合物作为有效成分的用于增强癌治疗剂的作用的药物(以下,记载为“本发明的第2药物”)。本发明的第2药物的给药对象是与本发明的第1药物的给药对象相同的患有在间质中产生CAF的浸润的恶性肿瘤的癌患者。因此,本发明的第2药物的给药对象能够通过上述本发明的癌患者选择方法进行选择。
作为使得在肿瘤组织细胞中过度表达meflin的组合物,能够优选使用包含能够表达地插入(expressively inserted)编码meflin的DNA(DNA encoding meflin)的质粒载体(plasmid vector)、病毒载体(viral vector)等的组合物。编码meflin的基因(geneencoding meflin)的碱基序列能够从公知的数据库(NCBI等)轻松获取。例如,人meflin基因(ISLR)的碱基序列的登记编号为NM_201526.2或NM_005545.4。表达meflin的质粒载体或病毒载体能够基于所获取到的人meflin基因(ISLR)的核苷酸序列,使用公知的基因工程技术来制备。
当以非病毒载体的形式给药使得在肿瘤组织细胞中过度表达meflin的组合物的情况下,能够利用如下方法等:使用脂质体导入meflin表达质粒的方法(脂质体法、HVJ-脂质体法、阳离子脂质体法、脂质转染法(lipofection)法、Lipofectamine法等)、微注射法(microinjection method)、利用基因枪(Gene Gun)将meflin表达质粒与载体(金属粒子)一同转移到细胞的方法。当以病毒载体的形式进行给药的情况下,通过将meflin表达盒(expression cassette)导入至经解毒的反转录病毒(Retroviridae)、腺病毒(Adenoviridae)、腺相关病毒、疱疹病毒(herpesvirus)、痘疮病毒(vaccinia virus)、痘病毒(poxvirus)、脊髓灰质炎病毒(poliovirus)、辛得比斯病毒(sindbis virus)、仙台病毒、SV40等DNA病毒或RNA病毒,然后用病毒载体感染靶肿瘤,由此能够导入meflin基因。作为本发明的第2药物的有效成分,优选含有meflin基因的病毒载体。
使得在肿瘤组织细胞中过度表达meflin的组合物的剂量优选考虑载体的种类、表达效率、肿瘤的大小等来适当设定。
本发明的第2药物为用于增强癌治疗剂的作用的药物,因此优选与癌治疗剂组合给药。所组合的癌治疗剂与上述本发明的第1药物中所使用的癌治疗剂相同。
〔诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与癌治疗剂的组合药物〕
本发明提供一种将诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与癌治疗剂组合来给药的治疗癌的药物(以下,记载为“本发明的第3药物”)。本发明的第3药物的给药对象是与本发明的第1药物的给药对象相同的患有在间质中产生CAF的浸润的恶性肿瘤的癌患者。因此,本发明的第3药物的给药对象能够通过上述本发明的癌患者选择方法来选择。
赖氨酰氧化酶(lysyl oxidase、以下记载为“LOX”)是将伯胺基质(primary aminesubstrate)氧化成反应性醛(reactive aldehyde)的含铜的胺氧化酶(amine oxidase)。赖氨酰氧化酶催化胶原蛋白中的肽基赖氨酸(peptidyl lysine)及羟基赖氨酸残基、以及弹性蛋白(elastin)中的肽基赖氨酸残基的氧化脱氨(oxidative deamination),是细胞外基质(matrix)的形成所必须的。产生的肽醛自发性缩合,并经历氧化反应,形成为了细胞外基质(matrix)的正常结构完整性所必须的源自赖氨酸的共价交联。
作为诱导癌间质中的LOX活性抑制的药剂,可以是直接抑制LOX的药剂,也可以是间接抑制LOX的药剂。直接抑制LOX的药剂包括:LOX抑制剂、抗LOX中和抗体等。LOX抑制剂的例子包括:西姆珠单抗(simtuzumab)等WO2011097513中所公开的抗体;GB2064等WO2016144703中所公开的化合物;PXS-5505、PXS-5446、PXS-6302等WO2020024017中所公开的化合物;PXS-5120A、PXS-5153A、PXS-5129A等WO2017136870中所公开的化合物;WO2017136871中所公开的氮杂吲哚卤代烯丙胺衍生物(azaindole haloallylaminederivatives);WO2018157190中所公开的卤代烯丙胺吡唑衍生物(haloallylaminepyrazole derivatives);WO2021012014中所公开的二氟卤代烯丙胺衍生物(difluorohaloallylamine derivatives);WO2011097513、WO2009017833、美国专利申请公开第2009/0053224号中所公开的抗体AB-0023;美国专利第4,965,288号、美国专利第4,997,854号、美国专利第4,943,593号、美国专利第5,021,456号、美国专利第5059714号、美国专利第5,120,764号、美国专利第5,182,297号、美国专利第5,252,608号、美国专利申请公开第2004/0248871号中所公开的化合物;PXS-5382A、PXS-5033A;PAT-1251(CAS编号:2007885-39-2)等。LOX抑制剂还包括与赖氨酰氧化酶活性部位的羰基反应,与羰基结合后生成通过共振稳定化的产物的伯胺,例如可举出下述伯胺:乙二胺、肼、苯肼及其衍生物、氨基脲及尿素衍生物、β-氨基丙腈(BAPN)或2-硝基乙胺等氨基腈、2-溴乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺、对卤代苄胺(p-halobenzylamines)等不饱和或饱和卤胺、以及硒代高半胱氨酸内酯(selenohomocysteine lactone)。此外,LOX抑制剂包括间接抑制剂,该间接抑制剂例如为如下化合物,即阻断赖氨酰及羟基赖氨酰残基被硫醇胺等赖氨酰氧化酶氧化脱氨而生成醛衍生物,例如可举出,D-青霉胺、或2-氨基-5-巯基-5-甲基己酸、D-2-氨基-3-甲基-3-((2-乙酰氨基乙基)二硫代)丁酸、对-2-氨基-3-甲基-3-((2-氨基乙基)二硫代)丁酸、4-((对-1-二甲基-2-氨基-2-羧乙基)二硫代)丁烷亚磺酸钠、2-乙酰氨基乙基-2-乙酰氨基乙硫醇磺酸酯、4-巯基丁烷亚磺酸钠三水合物等其类似物。
间接性抑制LOX的药剂的例子包括诱导恶性肿瘤的间质中的癌相关纤维原细胞的meflin表达的药剂等。本发明人等确认到meflin抑制LOX的活性(参阅实施例14)。此外,本发明人等确认到,通过用类维生素A来治疗被认为是CAF来源细胞的胰腺星形胶质细胞及间充质干细胞,meflin基因的表达水平上升(参阅实施例4、5);并且当向皮下移植胰腺癌细胞而形成肿瘤的小鼠给药类维生素A时,肿瘤内meflin基因的表达明显增加(实施例6)。因此,本发明的第1药物中所使用的类维生素A能够合适地用作间接抑制LOX的药剂。当在本发明的第3药物中使用类维生素A的情况下,类维生素A能够以与本发明的第1药物相同的方式实施。
而且,使得在肿瘤组织细胞中过度表达meflin的作为本发明的第2药物的有效成分的组合物也能够合适地用作间接抑制LOX的药剂。具体例包括:包含能够表达地插入编码meflin的DNA的质粒载体、病毒载体等的组合物等。当在本发明的第3药物中使用使得在肿瘤组织细胞中过度表达meflin的组合物的情况下,该组合物能够以与本发明的第2药物相同的方式实施。
已知LOX具有使胶原蛋白分子彼此交联的活性。认为通过胶原蛋白分子彼此交联,胶原蛋白纤维的强度增加,并且使组织硬化。因此认为,通过阻碍或抑制癌间质中的LOX的功能,癌组织的硬化得到抑制,扩张肿瘤血管,提高与其并用的癌治疗剂向肿瘤的递送,能够增强癌治疗剂的效果。本发明人等将该概念称为“间质调节”,认为通过预先对靶肿瘤进行“间质调节”之后来给药癌治疗剂,能够提高治疗效果。因此,本发明的第3药物中所使用的诱导癌间质中的LOX的活性抑制的药剂能够称为具有“间质调节”作用的药物。
本发明的第3药物中所使用的诱导癌间质中的LOX的活性抑制的药剂可以说是用于增强与其并用的癌治疗剂的药物的作用的有效成分,而且是用于促进与其并用的癌治疗剂向靶向肿瘤组织的递送的药物的有效成分。因此,在本发明包括以患有在间质中产生CAF的浸润的恶性肿瘤的癌患者为患者且以诱导癌间质中的赖氨酰氧化酶活性抑制的药剂为有效成分的用于增强癌治疗剂的作用的药物。而且,在本发明包括以患有在间质中产生CAF的浸润的恶性肿瘤的癌患者为患者且以诱导癌间质中的赖氨酰氧化酶活性抑制的药剂为有效成分的用于促进对靶向肿瘤组织的癌治疗剂递送的药物。
本发明的第3药物中所使用的癌治疗剂与上述本发明的第1药物中所使用的癌治疗剂相同。
用于诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与本发明的第3药物中所使用的癌治疗剂可以以下述方式对给药对象进行给药,即共同给药、或间隔一定时间分别分开来给药。在本说明书中,“组合给药”是指,诱导癌间质中的赖氨酰氧化酶活性抑制的药剂的适用时期和癌治疗剂的适用时期重叠,并不需要同时进行给药。在本发明的第3药物中,优选预先开始给药诱导癌间质中的赖氨酰氧化酶活性抑制的药剂,然后隔着时差开始给药癌治疗剂。开始给药诱导癌间质中的赖氨酰氧化酶活性抑制的药剂和开始给药癌治疗剂的时间差并没有特别限定,该时间差可以是1天以上、2天以上、3天以上、4天以上、5天以上、6天以上、7天以上。
虽不抑制LOX但具有“间质调节”作用的药剂的例子包括:WO2012012300中所公开的PEG化透明质酸降解酶(PEGylated hyaluronan degrading enzyme)PEGPH20等玻璃酸酶(hyaluronidase)制剂;US20180201640中所公开的4-甲基伞形酮(4-methylumbelliferone)衍生物等的透明质酸合成抑制剂;WO2006026430中所公开的IPI-926(Patidegib、Saridegib)、WO2007131201中所公开的sonidegib(Odomzo)、WO2006028958中所公开的vismodegib(Erivedge)、US2009005416中所公开的PF-04449913(Daurismo)、WO2010147917中所公开的LY-2940680(taladegib)、WO2009107850中所公开的NLM-001、WO2014001464中所公开的4SC-208等hedgehog信号抑制剂;WO2008009437、WO2009019007、WO2012031773中所公开的核酸药物NOX-A12等间质细胞衍生因子1抑制剂(stromal cell-derived factor 1inhibitor);WO2012049277、WO2016157149中所公开的化合物USL-311、WO2018011376中所公开的化合物LIT-927;WO2013048164中所公开的化合物IDF-11774、WO2005007828中所公开的化合物PX-478等低氧诱导因子1-α抑制剂(hypoxiainduciblefactor 1-alpha inhibitor);及WO2015035223中所公开的化合物PT-2977(Belzutifan)等低氧诱导因子2-α抑制剂(hypoxia inducible factor 2-alpha inhibitor)等。本发明还包括该种虽不抑制LOX但具有“间质调节”作用的药剂与癌治疗剂的组合药物。
本发明中包括下述各发明。
(1)一种药物,其以类维生素A与癌治疗剂的组合方式对通过上述本发明的选择方法选择的癌患者给药。
(2)一种癌治疗方法,该方法中,对通过上述本发明的癌患者选择方法选择的癌患者,将诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与癌治疗剂组合来给药。
(3)一种增强癌治疗剂作用的方法,该方法中,对通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者,给药类维生素A、使得在肿瘤组织细胞中过度表达meflin的组合物、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂。
(4)一种促进对靶向肿瘤组织的癌治疗剂递送的方法,该方法中,对通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者,组合给药类维生素A、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂。
(5)一种类维生素A、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂,其用于制造癌治疗用药物,其以通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者为对象。
(6)一种类维生素A、使得在肿瘤组织细胞中过度表达meflin的组合物、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂的用途,其用于制造用于增强癌治疗剂的作用的药物,其以通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者为对象。
(7)一种类维生素A、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂的用途,其用于制造用于促进对靶向肿瘤组织的癌治疗剂递送的药物,其中,所述药物以通过上述本发明的癌患者选择方法被选择且正在给药癌治疗剂的患者为对象。
(8)一种癌治疗用套组,其包含类维生素A及癌治疗剂,其中,类维生素A与癌治疗剂容纳在不同的容器中,并且所述癌患者通过上述本发明的癌患者选择方法被选择。
(9)一种癌治疗用类维生素A,其中,所述患者为通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者。
(10)一种癌治疗用诱导癌间质中的赖氨酰氧化酶活性抑制的药剂,其中,所述患者为通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者。
(11)一种类维生素A、使得在肿瘤组织细胞中过度表达meflin的组合物、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂的用途,其用于增强癌治疗剂的作用,所述患者为通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者。
(12)一种类维生素A、或诱导癌间质中的赖氨酰氧化酶活性抑制的药剂的用途,其用于促进对靶向肿瘤组织的癌治疗剂递送、其中,所述患者为通过上述本发明的癌患者选择方法选择且正在给药癌治疗剂的患者。
实施例
以下,通过实施例对本发明详细地进行说明,但本发明并不限定于这些。
〔实施例1:借由HE染色判定在间质中发生CAF的浸润的恶性肿瘤〕
使用通过手术或活检得到的肿瘤组织,按照常规方法制备组织标本,进行HE染色。病理诊断医生利用显微镜观察HE染色标本,从形态学上判定CAF的有无。
在图1~4中示出手术标本中的、间质中产生CAF的浸润的胰腺肿瘤的例子。图1是未分化癌、图2是胰腺导管内乳头状粘液腺癌、图3及图4是管状腺癌。在图1~4中,箭头表示CAF的位置。此外,在图5~14中示出手术标本中的、在间质中未产生CAF的浸润的胰腺肿瘤的例子。图5及图6是腺泡细胞癌、图7是胰腺导管内乳头状粘液腺癌(非侵袭性癌)、图8是胰腺导管内乳头状粘液腺瘤(IPMA)、图9是粘液性包囊肿瘤(mucinous cyst tumor)。图10是神经内分泌肿瘤(G1、胰岛素瘤)、图11是神经内分泌肿瘤(G1、胃泌素瘤)、图12是胰腺上皮内瘤变(PanIN)、图13是浆液性囊腺瘤、图14是实性假乳头状肿瘤(SPN)。另外,在任何图中,显微镜的放大倍数为上排100倍,下排200倍。
在图15~图17中示出活检标本中的、在间质中产生CAF的浸润的胰腺肿瘤的例子。图15是管状腺癌、图16是未分化癌、图17是胰腺导管内乳头状粘液腺癌(侵袭性癌)。此外,在图18~21中示出胰腺肿瘤活检标本中的、在间质中未产生CAF的浸润的胰腺肿瘤的例子。图18是腺泡细胞癌、图19是实性假乳头状肿瘤(SPN)、图20是神经内分泌肿瘤、图21是胰腺导管内乳头状粘液腺瘤(IPMA)。另外,在任何图中,显微镜的放大倍数为上排100倍,下排200倍。
〔实施例2:借由IHC或ISH判定在间质中产生CAF的浸润的恶性肿瘤〕
对由通过手术或胰腺肿瘤活检得到的肿瘤组织制备的组织标本,使用针对CAF的标志物分子的抗体进行IHC或使用与CAF标志物分子的mRNA杂交的探针进行ISH。通过在显微镜下进行观察,判定了阳性信号的有无。在本实施例中,采用meflin作为CAF的标志物分子,使用抗meflin抗体进行IHC及使用与meflin基因的mRNA杂交的探针进行ISH。
在图22及图23中示出meflin阳性胰腺肿瘤的例子,在图24中示出meflin阴性胰腺肿瘤的例子。所有的图均是对同一样品进行IHC和ISH而得的图像,高倍率为高倍放大视野(400倍)。在图22及图23中,箭头表示阳性细胞的位置。另外,在图24的IHC高倍率图像中,深染的圆形细胞是对坏死细胞的非特异性反应。
〔实施例3:他米巴罗汀对在间质中产生CAF的浸润的恶性肿瘤的肿瘤缩小效果〕
(1)实验方法
对BALB/c-nu雌性裸小鼠皮下移植人胰腺癌细胞BxPC-3(1.0×106个细胞),设为癌细胞单一移植组。此外,对BALB/c-nu雌性裸小鼠皮下移植人胰腺癌细胞BxPC-3(1.0×106个细胞)和人胰腺星形胶质细胞(5.0×106个细胞),设为共移植组。胰腺星形胶质细胞是胰腺的纤维原细胞,被认为是CAF的起源细胞。将癌细胞单一移植组及共移植组分别分为吉西他滨(Gem)和他米巴罗汀(AM80)给药组(Gem+AM80组)及Gem和DMSO给药组(Gem+DMSO组)这2组。从移植后第3天到第14天为止,每天口服给药AM80(3.0mg/kg)或DMSO。从移植后第6天起,每3天腹腔内给药1次Gem(50mg/kg)。在移植15天后测量肿瘤体积。将方案示于图25。
(2)结果
将结果示于图26。(A)是癌细胞单一移植组的结果、(B)是共移植组的结果。在癌细胞单一移植组中,在Gem+AM80组和Gem+DMSO组之间,没有观察到显著差异。在共移植组中,在Gem+AM80组中得到了显著的缩小效果。该结果表示,在间质中产生CAF的浸润的恶性肿瘤中,AM80增强抑癌剂的肿瘤缩小效果。
〔实施例4:类维生素A对人胰腺星形胶质细胞及小鼠间充质干细胞的重新编程效果〕
(1)实验方法
原代人胰腺星形胶质细胞使用了由东北大学·正宗博士(Dr.Masamune,To hokuUniversity)提供的细胞。原代小鼠间充质干细胞使用了从Cyagen Co.,Ltd.购入的细胞。胰腺星形胶质细胞及间充质干细胞均被认为是CAF的起源细胞。类维生素A使用了SCREEN-WELL Nuclear Receptor ligand library(ENZO)中所包含的类维生素A。将DMEM+10%FBS用作培养基。将细胞播种在胶原蛋白涂层培养皿中,培养至100%融合,并且以使浓度成为1μM的方式添加各种类维生素A。在48小时后回收细胞,使用RNeasyPLUS KIT(QIAGEN)提取RNA,并且使用ReverseTra Ace qPCR RT Master Mix(TOYOBO)来合成cDNA。使用Geneexpression assay(Thermo Fisher scientific),通过qPCR测量了meflin基因(ISLR及Islr)的表达水平。
(2)结果
将原代人胰腺星形胶质细胞的结果示于表1。ISLR表达水平以对照(DMSO处理细胞)的ISLR表达水平为1时的相对表达水平表示。所使用的类维生素A均使ISLR表达水平上升。在此可知,肿瘤促进性CAF的标志物是αSMA(基因名:Acta2),肿瘤抑制性CAF的标志物是meflin(基因名:Islr),这两种标志物在CAF中的表达水平成反比。因此,该结果表示,类维生素A将人的肿瘤促进性CAF重新编程为肿瘤抑制性CAF。
[表1]
类维生素A | ISLR表达水平(平均值) |
BADGE | 5089.576 |
AM580 | 3625.326 |
ATRA | 217.5011 |
阿曲汀(Acitretin) | 47.59336 |
TTNPB | 15.93748 |
13-顺式视黄酸 | 7.251799 |
9-顺式视黄酸 | 4.894304 |
乙酸视黄酯(Retinyl acetate) | 3.289829 |
4-羟基视黄酸 | 3.263734 |
DMSO(对照) | 1 |
将原代小鼠间充质干细胞的结果示于表2。Islr表达水平以对照(DMSO处理细胞)的Islr表达水平设为1时的相对表达水平表示。所使用的类维生素A均使Islr表达水平上升。在此,肿瘤促进性CAF的标志物是αSMA(基因名:Acta2),肿瘤抑制性CAF的标志物是meflin(基因名:Islr),这两种标志物在CAF中的表达水平成反比。因此,该结果表示,类维生素A将小鼠的肿瘤促进性CAF重新编程为肿瘤抑制性CAF。
[表2]
类维生素A | lslr表达水平(平均值) |
阿曲汀(Acitretin) | 7.65939471 |
阿达帕林(Adapalene) | 5.4284275 |
AM580 | 5.294880522 |
TTNPB | 5.183251296 |
4-羟基视黄酸 | 1.912238184 |
ATRA | 1.692915345 |
DMSO(对照) | 1 |
〔实施例5:类维生素A对小鼠间充质干细胞的重新编程效果〕
(1)实验方法
以与实施例4的使用原代小鼠间充质干细胞的实验相同的方法进行。作为类维生素A,使用了ATRA、AM80及AM580。通过qPCR测量了meflin基因(Islr)、肌动蛋白基因(Acta2)、I型胶原蛋白基因(Col1a1)及III型胶原蛋白基因(Col3a1)的表达水平。
(2)结果
将结果示于图27。(A)为meflin基因(Islr)的结果、(B)为肌动蛋白基因(Acta2)的结果、(C)为I型胶原蛋白基因(Col1a1)的结果、(D)为III型胶原蛋白基因(Col3a1)的结果。在对照(DMSO)中,Acta2、Col1a1及Col3a1的表达水平高,Islr的表达水平低。另一方面,类维生素A(ATRA、AM80、AM580)治疗组中,Islr的表达水平高,Acta2、Col1a1及Col3a1的表达水平低。该结果表示,肿瘤促进性CAF被类维生素A重新编程为肿瘤抑制性CAF。
〔实施例6:他米巴罗汀对小鼠胰腺癌细胞(AM80)的效果〕
(1)实验方法
mT5使用了由冷泉港实验室的Dr.David Tuveson分布的细胞,mT5是从作为自发性胰腺癌发病模型的KPC小鼠发病的胰腺肿瘤建立的胰腺癌细胞(人和小鼠胰腺导管癌的类器官模型(Organoid models of human and mouse ductal pancreatic cancer).Cell.2015Jan 15;160(1-2):324-38.doi:10.1016/j.cell.2014.12.021.Epub 2014Dec31.)。
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在8天后(第8天),对确认到肿瘤的形成的小鼠,将AM80口服给药15天。根据AM80的剂量(0.1mg/kg/天、0.5mg/kg/天、1mg/kg/天、3mg/kg/天),设为4个AM80给药组及1个对照组(给药DMSO)共计5组(各组n=5)。在AM80的给药开始前(第8天)、第11天、第15天、第18天、第22天,测量体重和肿瘤体积。在第22天,使小鼠安乐死,摘出肿瘤,制备组织标本,进行原位杂交(ISH)以检测meflin基因(Islr)表达及肌动蛋白基因(Acta2)表达,然后分别计数阳性信号数。进而,制备肿瘤的组织标本,利用抗CD31抗体对作为血管内皮细胞的标志物的CD31进行染色,并测量血管内腔面积。将方案示于图28。
(2)结果
(2-1)肿瘤体积
将肿瘤体积变化趋势示于图29。各组之间没有显著差异,即使给药任何浓度的AM80,都不会抑制胰腺癌细胞的增殖。此外,AM80的给药小鼠的体重不产生影响。
(2-2)肿瘤中的meflin基因(Islr)的表达
将利用ISH来检测肿瘤标本中的Islr表达的结果示于图30。(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较对照组及AM80的3mg/kg/天组中的每个高倍放大视野(400倍)的Islr阳性信号点数的图。通过给药AM80,作为抑制CAF的标志物的Islr的表达上升,AM80的3mg/kg/天组的Islr阳性信号的点数相比对照组明显多。
(2-3)肿瘤中的肌动蛋白基因(Acta2)的表达
将利用ISH来检测肿瘤标本中的Acta2表达细胞的结果示于图31。(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较对照组及AM80的3mg/kg/天组中的每高倍放大视野(400倍)的Acta2阳性信号点数的图。通过给药AM80,作为促进性CAF的标志物的Acta2的表达减少,AM80的3mg/kg/天组的Acta2阳性信号点数相比对照组明显少。
(2-4)使用抗CD31抗体对肿瘤标本的免疫染色
将利用CD31抗体对肿瘤标本进行免疫染色的结果示于图32。(A)是对照组的代表性显微图像、(B)是AM80的3mg/kg/天组的代表性显微图像、(C)是比较对照组和AM80的3mg/kg/天组的血管内腔面积的图。AM80的3mg/kg/天组的血管内腔面积相比对照组的血管内腔面积明显增加。
(2-5)总结
在C57BL/6J雌性小鼠的皮下移植小鼠胰腺癌细胞mT5而形成的肿瘤表达Islr或作为CAF标志物的Acta2,因此判定该肿瘤为在间质中产生CAF的浸润的恶性肿瘤。实施例6的结果表明,在存在促癌CAF的状态(对照组、Acta2阳性)下,间质内压高且血管由于压力而被挤压。当因给药AM80而重新编程为肿瘤抑制性CAF(Islr阳性)时,胶原蛋白产生等发生变化而引起间质的重塑,间质内压降低而被挤压的血管张开。
〔实施例7:他米巴罗汀与吉西他滨的组合使用对小鼠胰腺癌细胞的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在8天后(第8天),分为对照组、吉西他滨给药组(Gem组)及吉西他滨和他米巴罗汀给药组(Gem+AM80组)这3组(各组n=8),确保肿瘤体积均等。在Gem+AM80组中,从第8天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药17天。此外,在Gem组及Gem+AM80组中,在第15天、第18天及第21天,将吉西他滨(50mg/kg)分别腹腔内给药1次。在对照组中,代替他米巴罗汀,口服给药DMSO,代替吉西他滨,腹腔内给药生理食盐水。在AM80给药开始前(第8天)、第12天、第15天、第18天、第21天、第24天,测量肿瘤体积。将方案示于图33。
(2)结果
将结果示于图34。图34示出,Gem组相比对照组明显抑制肿瘤增殖,Gem+AM80组相比Gem组明显抑制肿瘤增殖。该结果表示,他米巴罗汀显著增强了吉西他滨的肿瘤增殖抑制效果。
〔实施例8:他米巴罗汀、吉西他滨及白蛋白结合型紫杉醇(nab-paclitaxel)的组合使用对人胰腺癌细胞的效果〕
(1)实验方法
对BALB/c-nu雌性裸小鼠,皮下移植人胰腺癌细胞BxPC-3(1.0×106个细胞)。在肿瘤体积达到50~150mm3时,分为对照组、吉西他滨和白蛋白结合型紫杉醇(nab-paclitaxel)给药组(Gem+nabPTX组)、以及吉西他滨、白蛋白结合型紫杉醇(nab-paclitaxel)及他米巴罗汀给药组(Gem+nabPTX+AM80组)这3组(各组n=7),确保肿瘤体积均等。在Gem+nabPTX+AM80组中,从分组当天(第1天)起,将他米巴罗汀(3.0mg/kg)1天1次口服给药17天。在Gem+nabPTX组及Gem+nabPTX+AM80组中,在第7天、第10天及第13天,分别腹腔内给药1次吉西他滨(50mg/kg),在第7天、第10天及第13天,分别静脉内给药1次白蛋白结合型紫杉醇(nab-paclitaxel)(5mg/kg)。在对照组中,代替他米巴罗汀,口服给药DMSO,代替吉西他滨,腹腔内给药生理食盐水,代替白蛋白结合型紫杉醇(nab-paclitaxel),静脉内给药生理食盐水。在AM80开始给药前(第1天)、第4天、第7天、第10天、第13天、第16天,测量肿瘤体积。将方案示于图35。
(2)结果
将结果示于图36。图36示出,Gem+nabPTX组相比对照组明显抑制肿瘤增殖,Gem+nabPTX+AM80组相比Gem+nabPTX组明显抑制肿瘤增殖。该结果表示,他米巴罗汀进一步显著增强了吉西他滨和白蛋白结合型紫杉醇(nab-paclitaxel)组合的肿瘤增殖抑制效果。
〔实施例9:他米巴罗汀与吉西他滨的组合使用对小鼠自发性胰腺癌发病模型(KPC小鼠)的效果〕
(1)实验方法
在小鼠自发性胰腺癌发病模型(KPC小鼠)(S.R.Hingorani et al.,Trp53R172Hand KrasG12D cooperate to promote chromosomal instability and widelymetastatic pancreatic ductal adenocarcinoma in mice.Cancer Cell 7,469-483(2005).)中,从通过腹部超声检查确认到胰腺肿瘤长度达到1mm以上的时点起(第1天),将他米巴罗汀(3.0mg/kg)1天1次口服给药17天。在吉西他滨和他米巴罗汀给药组(Gem+AM80组、n=5)中,在第7天、第10天及第13天,分别腹腔内给药1次吉西他滨(50mg/kg)。在对照组(Gem组、n=5)中,在第7天、第10天及第13天,分别腹腔内给药1次吉西他滨(50mg/kg),但不给药他米巴罗汀。在AM80给药开始前(第1天)、第8天、第15天、第22天,测量肿瘤长径。将方案示于图37。
(2)结果
将结果示于图38。图38示出,Gem+AM80组相比对照组(Gem组)明显抑制肿瘤增殖。KPC小鼠具有产生CAF的浸润的更丰富的间质,是最接近人胰腺肿瘤的小鼠模型。这表示,他米巴罗汀在该自发性发病模型中也显著增强了吉西他滨的肿瘤增殖抑制作用。
〔实施例10:他米巴罗汀与免疫检查点抑制剂的组合使用对小鼠自发性胰腺癌发病模型(KPC小鼠)的效果〕
(1)实验方法
代替吉西他滨使用抗PD1抗体或抗PDL1抗体,除此以外,以与实施例9相同的方法进行实验。其结果,他米巴罗汀和抗PD1抗体或抗PDL1抗体的组合组相比对照组(抗PD1抗体单一给药组或抗PDL1抗体单一给药组)明显抑制肿瘤增殖。
〔实施例11:他米巴罗汀与吉西他滨的组合使用对meflin缺陷型小鼠的效果〕
(1)实验方法
对meflin缺陷型小鼠(Maeda K.et al.,Sci Rep.2016Feb 29;6:22288.doi:10.1038/srep22288.),皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在8天后(第8天),分为吉西他滨单一给药组(Gem组、n=6)、吉西他滨和他米巴罗汀给药组(Gem+AM80组、n=6)这2组,确保肿瘤体积均等。在Gem+AM80组中,从第8天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药17天。在Gem+AM80组中,从第8天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药17天。在Gem组及Gem+AM80组中,在第15天、第18天及第21天,分别腹腔内给药1次吉西他滨(50mg/kg)。在AM80给药开始前(第8天)、第12天、第15天、第18天、第21天、第24天,测量体重和肿瘤体积。在第24天,使小鼠安乐死,摘出肿瘤,制备组织标本,进行原位杂交(ISH)以检测肌动蛋白基因(Acta2)表达,并且分别计数阳性信号。将方案示于图39。
(2)结果
(2-1)肿瘤体积
将肿瘤体积变化趋势示于图40。两组之间没有显著差异,吉西他滨和他米巴罗汀的组合使用没有抑制移植到meflin缺陷型小鼠的胰腺癌细胞的增殖。两组之间的体重也没有显著差异。
(2-2)肌动蛋白基因(Acta2)在肿瘤中的表达
将利用ISH来检测肿瘤标本中的Acta2表达细胞的结果示于图41。(A)是Gem组的代表性显微图像、(B)是Gem+AM80组的代表性显微图像、(C)是比较这两组的每个高倍放大视野(400倍)的Acta2阳性信号的点数的图。两组的阳性信号的点数没有观察到差异。该结果表示,他米巴罗汀经由meflin增强与其并用的抗癌剂的效果。
〔实施例12:meflin过度表达肿瘤的制备〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在肿瘤体积达到50~100mm3时,分为2组(各组n=7),确保肿瘤体积均等。在分组当天(第1天)、第5天及第9天,分别瘤内给药使得在感染细胞中过度表达meflin的仙台病毒(SeV-Meflin)、及使得在感染细胞中过度表达GFP的仙台病毒(SeV-GFP)。在第17天,测量肿瘤体积之后,使小鼠安乐死,摘出肿瘤,制备组织标本,进行原位杂交(ISH)以检测meflin基因(Islr)表达。将方案示于图42。
(2)结果
将ISH的结果示于图43。(A)是SeV-GFP组的代表性显微图像,(B)是SeV-Meflin组的代表性显微图像。在SeV-Meflin组中,meflin过度表达。将肿瘤体积变化趋势示于图44。两组之间没有显著差异。
〔实施例13:吉西他滨对meflin过度表达肿瘤的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在肿瘤体积达到50~100mm3时,分为2组(各组n=8)确保肿瘤体积均等。在分组当天(第1天)、第5天及第9天,分别瘤内给药使得在感染细胞中过度表达meflin的仙台病毒(SeV-Meflin)、使得在感染细胞中过度表达GFP的仙台病毒(SeV-GFP)。此外,在第5天、第8天、第11天及第14天,分别腹腔内给药1次吉西他滨(50mg/kg)。在第17天,测量肿瘤体积。将方案示于图45。
(2)结果
将结果示于图46。相比向SeV-GFP组给药吉西他滨,向SeV-Meflin组给药吉西他滨更明显抑制肿瘤增殖。该结果表示,通过向肿瘤导入meflin基因从而过度表达meflin,抑癌剂的效果增强。
当根据本发明的技术思想来选择的癌患者的情况下,将吉西他滨与除了他米巴罗汀以外的其他类维生素A组合使用时,也显示出类似效果。此外,将他米巴罗汀与除了吉西他滨以外的其他癌治疗剂组合使用的情况下,也显示出类似效果。此外,将除了他米巴罗汀以外的其他类维生素A与除了吉西他滨以外的其他癌治疗剂组合使用的情况下,也显示出类似效果。这些效果能够根据上述的实施例轻松确认。
〔实施例14:meflin的功能分析1〕
(1)实验方法
收集对照的Flp-In-293细胞或稳定表达小鼠meflin的细胞的培养上清液(分别称为对照条件培养基、meflin条件培养基)。接着,以指定浓度将每种条件培养基与重组人LoxL2(recombinant human LoxL2)进行混合,使用LOX活性测定试剂盒(Abcam公司,ab112139),对LOX活性进行定量。使用LOXL2是因为重组LOX没有活性。
(2)结果
将结果示于图47。该结果表示,meflin明显抑制LOX活性。
〔实施例15:meflin的功能分析2〕
(1)实验方法
使用作为小鼠自发性胰腺癌发病模型的KPC小鼠(野生型)和meflin缺陷型KPC小鼠(Maeda K,et al.Identification of Meflin as a potentialmarker formesenchymal stromal cells.Sci Rep 2016;6:22288.)(各组n=6)。使因肿瘤导致濒临死亡的小鼠(15~24周龄)安乐死,摘出胰腺,制备肿瘤的组织标本。从肿瘤的组织标本随机选择8~16张图像,利用二次谐波显微镜测量胶原蛋白的排列,并计算曲率系数(coefficientof curvature)以分析胶原蛋白的线性。
(2)结果
将结果示于图48。(A)是野生型KPC组的代表性二次谐波显微图像、(B)是meflin缺陷型KPC组的代表性二次谐波显微图像、(C)是比较这两组的胶原蛋白的曲率系数的图,图中N为观察视野数量。
〔实施例16:他米巴罗汀对肿瘤间质中的胶原蛋白的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在8天后(第8天),分为对照组及他米巴罗汀给药组(AM80组)这2组(各组n=5),确保肿瘤体积均等。在AM80组中,从第8天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药7天。在对照组中,代替他米巴罗汀,口服给药DMSO。在第15天,使小鼠安乐死,摘出肿瘤,制备组织标本。从肿瘤的组织标本随机选择8~16张图像,利用二次谐波显微镜测量胶原蛋白的排列,并分析曲率(线性)。
(2)结果
将结果示于图49。(A)是对照组的代表性二次谐波显微图像、(B)是AM80组的代表性二次谐波显微图像、(C)是比较这两组的胶原蛋白的曲率(线性)的图。该结果表示,在对照组中,胶原蛋白的线性明显增加。从该结果可知,在AM80组中,给药他米巴罗汀可诱导CAF中meflin的表达,并抑制间质中的LOX活性,由此胶原蛋白的线性降低。
〔实施例17:他米巴罗汀和吉西他滨的给药时期带来的效果的检讨〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在8天后(第8天),分为吉西他滨单一给药组(Gem组)、他米巴罗汀预先给药+吉西他滨给药组(AM80预先+Gem组)、以及他米巴罗汀预先/共同给药+吉西他滨给药组(AM80预先&共同+Gem组)这3组(各组n=5),确保肿瘤体积均等。关于他米巴罗汀预先给药,从第8天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药7天。关于他米巴罗汀的共同给药,从第15天起,将他米巴罗汀(3.0mg/kg)1天1次口服给药10天。关于吉西他滨(50mg/kg),在第15天、第18天及第21天,分别腹腔内给药1次。在不给药他米巴罗汀的小鼠(Gem组)中,在预先/共同给药他米巴罗汀的同一天,口服给药DMSO。在AM80给药开始前(第8天)、第12天、第15天、第18天、第21天、第24天,测量肿瘤体积。将方案示于图50。
(2)结果
将肿瘤体积变化趋势示于图51。该结果表示,AM80预先+Gem组与AM80预先&共同+Gem组同等程度地抑制肿瘤增殖。
〔实施例18:组合使用他米巴罗汀、吉西他滨及免疫检查点抑制剂的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在移植后第8天,分为抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这2组(各组n=7),确保肿瘤体积均等。将分组当天设为第1天,从第1天起,将他米巴罗汀(3mg/kg)1天1次口服给药7天。在第7天腹腔内给药吉西他滨(100mg/kg),在第8天、第10天、第12天、第14天、第16天及第18天腹腔内给药抗PD-L1抗体(10F.9G2)250μg/匹。从第1天、第4天、第7天到第27天为止,每隔1天测量肿瘤体积。将方案示于图52。另外,确认所有小鼠的死亡为止的存活率。
(2)结果
将肿瘤体积变化趋势示于图53。该结果表示,与PDL1组相比,PDL1+AM80组明显抑制肿瘤增殖。将存活率变化趋势示于图54。该结果表示,与PDL1组相比,PDL1+AM80组的生存期明显延长。
〔实施例19:组合使用他米巴罗汀与免疫检查点抑制剂的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在移植后第8天,分为对照组、抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这3组(各组n=7),确保肿瘤体积均等。将分组当天设为第1天,从第1天起,将他米巴罗汀(3mg/kg)1天1次口服给药7天。在第8天、第10天、第12天、第14天、第16天及第18天,以250μg/匹腹腔内给药抗PD-L1抗体(10F.9G2)。对照组中,代替抗PD-L1抗体给药IgG。从第8天到第26天为止,每隔1天测量肿瘤体积。将方案示于图55。另外,确认所有小鼠的死亡为止的存活率。
(2)结果
将肿瘤体积变化趋势示于图56。该结果表示,与PDL1组相比,PDL1+AM80组明显抑制肿瘤增殖。将存活率变化趋势示于图57。该结果表示,与PDL1组相比,PDL1+AM80组的生存期明显延长。
〔实施例20:他米巴罗汀与免疫检查点抑制剂的组合使用对膀胱癌的效果〕
(1)实验方法
对C57BL/6J雌性小鼠,皮下移植小鼠膀胱癌细胞MB49(1.0×106个细胞)(第1天)。在第5天,分为抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这2组(各组n=5),确保肿瘤体积均等。从第5天起,将他米巴罗汀(3mg/kg)1天1次口服给药7天。在第12天、第15天、第18天及第21天,以250μg/匹腹腔内给药抗PD-L1抗体(10F.9G2)。从第2天到第40天为止,每3天测量1次肿瘤体积。将方案示于图58。
(2)结果
将肿瘤体积变化趋势示于图59。该结果表示,与PDL1组相比,PDL1+AM80组明显抑制肿瘤增殖。
〔实施例21:他米巴罗汀与免疫检查点抑制剂的组合使用对肺癌的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植使得在作为小鼠肺癌细胞株的Lewis lungcarcinoma cell line(路易士肺腺癌细胞)(LCC)中强制表达荧光素酶(Luciferase)的细胞LCC-luc(1.0×106个细胞)(第1天)。在第5天,分为抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这2组(各组n=5),确保肿瘤体积均等。从第9天起,将他米巴罗汀(3mg/kg)1天1次口服给药7天。在第16天、第19天及第22天,以250μg/匹腹腔内给药抗PD-L1抗体(10F.9G2)。从第9天到第40天为止,每3天测量1次肿瘤体积。
(2)结果
将肿瘤体积变化趋势示于图60。该结果表示,与PDL1组相比,PDL1+AM80组明显抑制肿瘤增殖。
〔实施例22:他米巴罗汀与免疫检查点抑制剂的组合使用对胃癌的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胃癌细胞株YTN5或YTN16(1.0~5.0×106个细胞)(第1天)。在第5天,分为抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这2组(各组n=5),确保肿瘤体积均等。在第5天-第9天中的任一天,开始给药他米巴罗汀。他米巴罗汀以1天1次3mg/kg,口服给药7天。从他米巴罗汀的给药结束第2天起,每3天1次,以250μg/匹、合计3次或6次腹腔内给药PD-L1抗体(10F.9G2)。从他米巴罗汀的给药开始起,每3天测量1次肿瘤体积。与PDL1组比较,PDL1+AM80组明显抑制肿瘤增殖。
〔实施例23:他米巴罗汀与免疫检查点抑制剂的组合使用对meflin缺陷型小鼠的效果〕
(1)实验方法
对meflin缺陷型小鼠(Maeda K.et al.,Sci Rep.2016Feb 29;6:22288.doi:10.1038/srep22288.)皮下移植小鼠胰腺癌细胞mT5(1.0×106个细胞)。在移植后第8天,分为对照组、抗PD-L1抗体给药组(PDL1组)及抗PD-L1抗体和他米巴罗汀给药组(PDL1+AM80组)这3组(各组n=7),确保肿瘤体积均等。将分组当天设为第1天,从第1天起,将他米巴罗汀(3mg/kg)1天1次口服给药7天。在第8天、第10天、第12天、第14天、第16天及第18天,以250μg/匹腹腔内给药抗PD-L1抗体(10F.9G2)。对照组中,代替抗PD-L1抗体给药IgG。从第8天到第26天为止,每隔1天测量肿瘤体积。将方案示于图61。另外,确认所有小鼠的死亡为止的存活率。
(2)结果
将肿瘤体积变化趋势示于图62。该结果表示,在PDL1组与PDL1+AM80组之间,抑制肿瘤增殖的效果没有显著差异。将存活率变化趋势示于图63。该结果表示,在PDL1组与PDL1+AM80组之间,存活率没有显著差异。
〔实施例24:他米巴罗汀与免疫检查点抑制剂的组合使用对胃癌的效果〕
(1)实验方法
对C57BL/6J雌性小鼠皮下移植小鼠胃癌细胞株YTN5(5.0×106个细胞)(第1天)。在第7天,分为抗PD1抗体给药组(PD1组)及抗PD1抗体和他米巴罗汀给药组(PD1+AM80组)这2组(各组n=6),确保肿瘤体积均等。在第7天,开始给药他米巴罗汀。他米巴罗汀以1天1次、3mg/kg,口服给药6天。从他米巴罗汀的给药结束第2天起,每3天1次,以200μg/匹、合计3次腹腔内给药PD1抗体(10F.9G2)。从他米巴罗汀的给药开始起,每3天测量1次肿瘤体积。
(2)结果
将肿瘤体积变化趋势示于图64。该结果表示,与PD1组相比,PD1+AM80组明显抑制肿瘤增殖。
另外,本发明并不限定于上述各实施方式及实施例,在权利要求的范围内能够进行各种变更。对于通过将不同的实施方式中分别公开的技术适当组合的方法而得到的实施方式也包含在本发明的技术范围。本说明书中所记载的所有学术文献及专利文献的内容作为参考而全部引入到本说明书中。
Claims (21)
1.一种类维生素A与癌治疗剂的组合疗法有效的癌患者的选择方法,所述方法包括选择患有在间质中产生癌相关纤维原细胞的浸润的恶性肿瘤的癌患者的步骤。
2.根据权利要求1所述的方法,其中,
所述选择癌患者的步骤包括在从受检癌患者得到的恶性肿瘤组织中检测至少1个癌相关纤维原细胞。
3.根据权利要求1或2所述的方法,其中,
所述选择癌患者的步骤包括制备从受检癌患者得到的恶性肿瘤组织的病理组织标本,在显微镜观察下检测至少1个癌相关纤维原细胞。
4.根据权利要求1至3中任一项所述的方法,其中,
所述选择癌患者的步骤包括在显微镜下观察从受检癌患者得到的恶性肿瘤组织的病理组织标本,在包含癌细胞区域和间质区域的任意高倍放大视野中检测至少1个癌相关纤维原细胞。
5.根据权利要求3或4所述的方法,其中,
癌相关纤维原细胞的检测是通过显微镜观察经苏木精-伊红染色的病理组织标本来进行。
6.根据权利要求3或4所述的方法,其中,
癌相关纤维原细胞的检测是通过对癌相关纤维原细胞的标志物分子的免疫组织化学染色或原位杂交来进行。
7.一种药物,其以通过权利要求1至6中任一项所述的方法选择的癌患者为对象,并且将类维生素A与癌治疗剂组合来给药。
8.根据权利要求7所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
9.根据权利要求7或8所述的药物,其中,
所述类维生素A为他米巴罗汀。
10.根据权利要求7至9中任一项所述的药物,其中,
所述类维生素A以预先给药的方式使用。
11.一种用于增强癌治疗剂的作用及/或用于促进对靶向肿瘤组织的癌治疗剂递送的药物,其以通过权利要求1至6中任一项所述的方法选择的癌患者为对象,并且以类维生素A为有效成分。
12.根据权利要求11所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
13.根据权利要求11或12所述的药物,其中,
所述类维生素A为他米巴罗汀。
14.一种用于增强癌治疗剂的作用的药物,其以通过权利要求1至6中任一项所述的方法选择的癌患者为对象,并且以使得在肿瘤组织细胞中过度表达meflin的组合物为有效成分。
15.根据权利要求14所述的药物,其中,
所述使得过度表达meflin的组合物为含有meflin基因的病毒载体。
16.根据权利要求14或15所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
17.一种药物,其以通过权利要求1至6中任一项所述的方法选择的癌患者为对象,并且将诱导癌间质中的赖氨酰氧化酶活性抑制的药剂与癌治疗剂组合来给药。
18.根据权利要求17所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
19.根据权利要求17或18所述的药物,其中,
预先使用诱导癌间质中的赖氨酰氧化酶活性抑制的药剂。
20.一种用于增强癌治疗剂的作用及/或用于促进对靶向肿瘤组织的癌治疗剂递送的药物,其以通过权利要求1至6中任一项所述的方法选择的癌患者为对象,并且以诱导癌间质中的赖氨酰氧化酶活性抑制的药剂为有效成分。
21.根据权利要求20所述的药物,其中,
所述癌治疗剂为化学治疗剂、分子靶向剂、免疫治疗剂或激素治疗剂。
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