CN113082212A - 包含mTOR抑制剂的药物组合物及其应用 - Google Patents
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Abstract
本发明提供了一种治疗癌症尤其是阴茎癌的药物组合物,所述药物组合物包含mTOR抑制剂。本发明经过长期大量的研究发现,mTOR通路抑制剂在体内、外均能对阴茎癌细胞产生显著的生长抑制作用,而作为对照,目前临床使用的含铂化疗方案(顺铂+紫杉醇)在实验过程中并未体现出明确的治疗作用,由此确定了mTOR抑制剂在治疗阴茎癌方面的功能及潜在价值。本发明为阴茎癌,尤其是晚期阴茎癌提供了一种新的靶向治疗方案,能够有效扩大阴茎癌的用药谱,改善阴茎癌治疗方案单一的现状。本发明对于改善阴茎癌的预后有重要作用,具有十分重要的临床意义和社会意义。
Description
技术领域
本发明属于肿瘤治疗技术领域,具体涉及一种包含mTOR抑制剂的药物组合物及其应用。
背景技术
阴茎癌在全球范围内是一种罕见的男性恶性肿瘤。阴茎癌的预后与其转移状态密切相关,对于早期/局部晚期阴茎癌,单纯手术治疗/新辅助化疗+手术治疗往往能取得较好的疗效,但对于晚期阴茎癌,特别是发生远处转移的患者,其预后极差。目前,对于转移性阴茎癌,NCCN指南批准的一线治疗方案仅有TIP(紫杉醇+异环磷酰胺+顺铂),二线治疗方案有PD-1抗体帕博丽珠单抗和EGFR抗体西妥昔单抗。由此可见阴茎癌的系统治疗方案较为单一,特别是在靶向药领域有待开发。
小分子靶向药多是针对肿瘤中的癌基因及其信号通路中关键分子的特异性抑制剂。其作用机制是阻断肿瘤中的关键信号通路的传导从而抑制肿瘤生长、促进凋亡,达到治疗肿瘤的目的。阴茎癌中靶向药的应用鲜见报道,到目前为止,只有靶向表皮生长因子受体(EGFR)的抑制剂被尝试应用于晚期转移性阴茎癌的姑息性治疗。现有的研究表明,阴茎癌的遗传学特征中,除了常见EGFR的突变可作为治疗靶点外,还存在诸如CDK4、PIK3CA、DDR(DNA damage repair)通路、NOTCH1通路等分子/信号通路的改变,这也说明了阴茎癌中可能还有其它的潜在治疗靶点,对其进行研究将对扩大阴茎癌的用药谱、改善阴茎癌的预后有重要意义。
然而,上述研究多数仅处于理论假设阶段,并没有针对阴茎癌的新靶点或新通路研发出新的药物或治疗方案,因而对于临床阴茎癌尤其是晚期阴茎癌的治疗缺乏实质性的指导作用,从而导致其治疗方案停滞不前,仍然采用较为传统的化疗方案。阴茎癌一旦化疗失败,就会面临无药可用的困境,因此扩大阴茎癌的用药谱是一个急需解决的临床问题,这将有效改善晚期阴茎癌的预后。
发明内容
针对上述存在问题和不足,本发明提供一种包含mTOR抑制剂的药物组合物,以解决现有技术中阴茎癌治疗方案单一、治疗效果差、预后差等问题,从而有效拓宽阴茎癌的用药谱,改善其治疗效果,为阴茎癌的临床用药和治疗提供新的理论依据和实验基础。
本发明是通过如下技术方案得以实现的:
本发明第一方面提供了一种治疗癌症的药物组合物,所述药物组合物包含mTOR抑制剂。
作为优选地,所述癌症选自阴茎癌、肾癌、肺癌、肠癌、胃癌、食管癌、肝癌、宫颈癌、乳腺癌、白血病、恶性淋巴瘤、鼻咽癌、胰腺癌中的一种或多种。
作为优选地,所述癌症选自阴茎癌。
作为优选地,所述阴茎癌为阴茎鳞状细胞癌。
作为优选地,所述mTOR抑制剂选自雷帕霉素(Rapamycin)、依维莫司(Everolimus)、替西罗莫司(Temsirolimus)、Ridaforolimus、AZD-8055中的一种或多种。
作为优选地,所述药物组合物中还包含紫杉醇、顺铂、环磷酰胺、异环磷酰胺、蛋白酶体抑制剂、RTK抑制剂中的一种或多种。
作为优选地,所述RTK抑制剂选自尼洛替尼(Nilotinib)、吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)、拉帕替尼(Lapatinib)、阿法替尼(Afatinib)、达可替尼(Dacomitinib)、凡德他尼(Vandetanib)、来那替尼(Neratinib)、奥希替尼(Osimertinib)、阿帕替尼(Apatinib)、阿西替尼(Axitinib)中的一种或多种。
本发明第二方面提供了mTOR抑制剂在制备治疗癌症药物中的应用。
作为优选地,所述癌症选自阴茎癌、肾癌、肺癌、肠癌、胃癌、食管癌、肝癌、宫颈癌、乳腺癌、白血病、恶性淋巴瘤、鼻咽癌、胰腺癌中的一种或多种。
作为优选地,所述癌症选自阴茎癌。
作为优选地,所述阴茎癌为阴茎鳞状细胞癌。
作为优选地,所述mTOR抑制剂选自雷帕霉素(Rapamycin)、依维莫司(Everolimus)、替西罗莫司(Temsirolimus)、Ridaforolimus、AZD-8055中的一种或多种。
mTOR抑制剂是一类重要的抗肿瘤药物,目前该类抑制剂中已上市的仅为第一代药物。以Rapamycin为代表的第一代mTOR抑制剂,其作用机制是诱导FKBP12与mTOR结合,阻碍mTORC1复合体的形成,从而抑制其功能。最初,Rapamycin作为免疫抑制剂用于应对肾移植术后排斥反应。但是,Rapamycin稳定性差,限制了其临床应用,因此,Temsirolimus,Everolimus,Ridaforolimus等一系列Rapamycin的结构衍生药物被研发。
Temsirolimus作为前药进入肝脏后,被CYP3A4水解成Rapamycin。目前,Temsirolimus被批准用于晚期肾癌与套细胞淋巴瘤的治疗。此外该药在多个癌种都进行过临床试验,如治疗复发性/含铂方案耐药性卵巢癌和复发性子宫内膜癌,联合伊立替康治疗儿童复发性神经母细胞瘤。Everolimus应用相对广泛,可用于晚期转移性/复发性肾细胞癌、结节性硬化、胰腺神经内分泌肿瘤、室管膜下巨细胞星型细胞瘤、内分泌治疗耐药的HR+&HER2-乳腺癌等疾病的治疗。Ridaforolimus目前处于临床试验中,对骨、软组织肉瘤和复发转移性子宫内膜癌都有一定疗效,但尚未进入指南。
第二代mTOR抑制剂的研发方向是竞争性结合mTOR的ATP结合位点,因此会同时抑制mTORC1和mTORC2,又由于PI3K与mTOR的酶活性结构与有很大的同源性,因此可以同时抑制PI3K和mTOR。由于第二代抑制剂的毒副作用较大,目前尚无药物进入III期临床试验。第三代mTOR抑制剂的研发方向较为多样化,目前均处于临床前研究阶段。
由此可见,现有技术中对于mTOR抑制剂的研究并不活跃,且可用的药物种类选择为数不多,在阴茎癌方面的研究更是未曾开展。本发明发明人经过长期大量的研究,建立了多个阴茎鳞状细胞癌细胞株,并利用5株细胞在细胞水平对阴茎癌的潜在靶向药物进行了筛选,所选小分子药物库包括58种FDA批准上市及目前正处于研究阶段的26种小分子靶向药,并且发明人还选取了12种临床常用化疗药物作为对照。在筛选及评价过程中发现,mTOR通路抑制剂在体内、外均能对阴茎癌细胞产生显著的生长抑制作用,而作为对照,含铂化疗方案(顺铂+紫杉醇)在实验过程中并未体现出明确的治疗作用,由此确定了mTOR抑制剂在治疗阴茎癌方面的潜在应用价值。
本发明与现有的技术相比,具有如下有益效果:
(1)本发明通过大量的实验筛选并验证了mTOR通路抑制剂能有效的抑制阴茎癌在体内、外的增殖、生长过程,其可作为晚期阴茎癌的一种新的治疗方案,并且此类抑制剂可采用口服的给药方式,在动物模型中的使用安全性也获得有效的验证。
(2)本发明给阴茎癌提供了一种新的靶向治疗方案,能够有效扩大阴茎癌治疗中的用药谱,改善阴茎癌治疗方案单一的现状。在此研究基础上,可开发更多更有效的“综合治疗”方案,改善预后,为阴茎癌的精准治疗进展提供有力的实验数据支撑,具有十分重要的临床意义和社会意义。
附图说明
图1 为实施例1 雷帕霉素与化疗方案对阴茎癌细胞(Penl-2)体内生长的抑制效果评价(采用体积生长曲线表示)。
图2 为实施例1所有个体(实验鼠)肿瘤体积生长曲线。
图3为青蒿琥酯、雷帕霉素、拉帕替尼、阿法替尼、卡非佐米和奥西替尼等6种分子靶向药与化疗方案对阴茎癌细胞(149RCa)体内生长的抑制效果评价(采用体积生长曲线表示)。
图4为雷帕霉素与化疗方案对应个体(实验鼠)肿瘤体积生长曲线。
图5为实施例3第34天肿瘤体积分析。
图6为实施例3第34天摘除的实验鼠荷瘤重量分析。
图7为实施例3阴茎癌细胞(149RCa)各类药物治疗过程中实验鼠重量时间变化曲线。
图8 为实施例3阴茎癌细胞(149RCa)各类药物治疗后荷瘤实体图。
具体实施方式
为使本发明的目的、技术方案及效果更加清楚、明确,以下参照实施例对本发明作进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
在无特殊说明的情况下,本发明上下文中所列出的包括Penl-1、Penl-2、149RCa、149RM和LM156等阴茎鳞状细胞癌细胞系均按照现有技术进行培养,所有细胞系均通过中国典型培养物保藏中心(武汉)短串联重复分析鉴定,并使用PCR检测试剂盒(上海BiothriveSci)验证是否存在支原体污染,同时在液氮中冷冻保存并用于后续实验。本发明所使用的试剂中,均通过市售获得。
生物学重复中选择具有代表性的结果呈现在上下文附图中,数据按照图示中规定的以mean±SD和mean±SEM展示。所有体外实验至少重复三次,动物实验重复两次。数据采用GraphPad Prism 8.0或SPSS 22.0软件进行分析。采用t检验或方差分析比较两组或两组以上的平均值差异,p<0.05被认为是一个显著的差异。
实施例1 细胞体外增殖抑制实验
(1)取对数生长期的Penl-1、Penl-2、149RCa、149RM和LM156细胞按一定密度(3000-5000/孔)接种于96孔板中;
(2)24小时后弃旧培养基,将细胞分别用含有不同浓度药物的培养基进行处理;其中所采用的药物分别为AZD-8055、Rapamycin、Everolimus、Temsirolimus、紫杉醇(Taxol)及顺铂(DDP),药物浓度梯度分别为100μM、20μM、4μM、0.8μM、0.16μM、0.032μM、0.0064μM、0.00128μM和0μM,组10为空白组不接种细胞;
(3)培养48小时后每孔加入5mg/mL MTT溶液20μL,置于37℃孵箱中避光孵育4小时,小心弃去培养基,尽量不要吸到孔底的甲瓒,加入DMSO将甲瓒溶解,置于摇床低速震荡10分钟,用酶标仪检测490nm波长处的OD值。
以0μM药物组为对照组,细胞存活率=(加药组OD值-空白组OD值)/(对照组OD值-空白组OD值)×100%,比较各种药物处理后细胞的存活情况,并计算每种药物在5种细胞中的IC50。
结果如下表1所示,结果显示,mTOR通路相关抑制剂AZD-8055、Rapamycin、Everolimus和Temsirolimus均对五株细胞具有明显的增殖抑制作用,其中AZD-8055、Rapamycin和Everolimus的IC50在5个细胞株中均低于2μM;Temsirolimus由于为前药,需经代谢水解为雷帕霉素从而发挥作用,因而其IC50并非如其他几种mTOR抑制剂那么显著。
而阴茎癌的标准TIP(紫杉醇+异环磷酰胺+顺铂)化疗方案中的紫杉醇极为有效(IC50<0.1μM),但顺铂对阴茎癌细胞的增殖抑制效果一般。异环磷酰胺为前体药,需经肝脏代谢成为活性形式才具备抗肿瘤作用,故未纳入实验。
由此可见,mTOR抑制剂确实能对阴茎癌细胞产生非常显著的杀伤作用。
表1 不同化合物对于阴茎癌细胞增殖抑制的影响(IC50,μM)
Penl-1 | Penl-2 | 149RCa | 149RM | LM156 | |
AZD-8055 | 0.034±0.001 | 0.003±0.001 | 0.097±0.004 | 0.03±0.003 | <0.001 |
Rapamycin | 1.562±0.292 | 0.859±0.166 | 0.22±0.083 | 0.139±0.068 | 0.181±0.008 |
Everolimus | 0.13±0.018 | 0.684±0.156 | 0.277±0.058 | 0.085±0.018 | 1.334±0.288 |
Temsirolimus | 6.284±1.262 | 79.082±6.7 | 31.788±6.714 | 22.24±1.666 | 9.445±0.828 |
Taxol | 0.001±0.000 | <0.001 | <0.001 | 0.001±0.00 | 0.084±0.011 |
DDP | 8.661±0.82 | 10.817±0.882 | 10.238±1.007 | 14.992±1.786 | 24.337±6.002 |
实施例2 Penl-2体内抗肿瘤实验
为进一步确认mTOR抑制剂在阴茎癌中的效果,选择了雷帕霉素作为示例以验证其在体内的抗肿瘤效果。
选择4-6周龄左右雄性裸鼠进行Penl-2细胞皮下移植瘤生长抑制实验,具体实验方法如下:
(1)体外培养Penl-2细胞,搜集对数生长期细胞消化、离心,用PBS重悬;
(2)将4×106细胞分别接种至2只裸鼠右侧肩胛部皮下,待其成瘤后,将瘤体取出,均匀分成体积约为5mm3大小的瘤块;
(3)将获得的瘤块重新移植到若干新的裸鼠皮下,待成瘤后,将21只裸鼠随机分为3组,每组7只,采用灌胃给药或腹腔注射给药。
具体给药方案如下(每周):组1灌胃给予生理盐水(day1-7),组2腹腔注射化疗药物紫杉醇(Taxol,TAX)5mg/kg (day1)+顺铂(Cis-platinum,DDP)10mg/kg (day3、day6),组3灌胃给药雷帕霉素(Rapamycin) 5mg/kg•day(day1-7)。共计给药3周,每2天测量一次肿瘤长径(a)与短径(b)。
肿瘤体积计算公式为:V=1/2×a×b2
结果如图1所示。根据对肿瘤体积的连续测量结果,组2肿瘤体积未见缩小,甚至略有增大,而组3与组1、组2相比,体积显著缩小。图2所示是每一肿瘤个体的生长曲线,与空白组和化疗组相比,Rapamycin组的所有肿瘤生长都明显缓慢。由此可见,mTOR抑制剂在体内确实能够对阴茎癌产生非常显著的抑制作用,这也与前面的细胞实验结果相匹配。
实施例3 149RCa体内抗肿瘤实验
为了进一步确认mTOR抑制剂对体内阴茎癌的抑制效果,进一步选择了149RCa细胞系进行体内肿瘤模型的构建,同时在实施例2用药方案的基础上,进一步使用青蒿琥酯(Artesunate)、拉帕替尼(Lapatinib)、阿法替尼(Afatinib)、卡非佐米(Carfilzomib)及奥希替尼(Osimertinib,AZD-9291)进行同步实验,从而充分验证并比较mTOR抑制剂对于阴茎癌体内抑制作用及相较于其他抗肿瘤药物的抑制效果。
选择4-6周龄左右雄性裸鼠进行149RCa细胞皮下移植瘤生长抑制实验,具体实验方法如下:
(1)体外培养149RCa细胞,搜集对数生长期细胞消化、离心,用PBS重悬;
(2)将4×106细胞接种至3只裸鼠右侧肩胛部皮下,待其成瘤后,将瘤体取出,均匀分成体积约为5mm3大小的瘤块;
(3)将获得的瘤块重新移植到若干新的裸鼠皮下,待成瘤后,将80只裸鼠随机分为8组,每组10只,进行灌胃给药或腹腔注射给药。
具体给药方案如下(每周):组1灌胃给予生理盐水(day1-7),组2腹腔注射化疗药物紫杉醇10mg/kg (day1)+顺铂15mg/kg (day3、day6),组3灌胃给药雷帕霉素(Rapamycin)5mg/kg•day(day1-7),组4腹腔注射给药青蒿琥酯(Artesunate) 100mg/kg·day (day1-7),组5灌胃给药拉帕替尼(Lapatinib) 150 mg/kg·day (day1-7),组6灌胃给药阿法替尼(Afatinib) 15 mg/kg·day (day1-5),组7腹腔注射给药卡非佐米(Carfizomib) 5 mg/kg(day1、day5),组8灌胃给药奥西替尼(Osimertinib, AZD-9291) 5 mg/kg·day (day1-7)。共计给药3周,每2天测量一次肿瘤长径(a)与短径(b),计算肿瘤体积。
结果如图3-8所示。根据对肿瘤体积的连续测量结果,雷帕霉素组的肿瘤体积显著小于其他组,尤其相对于紫杉醇顺铂联合用药组、青蒿琥酯组、拉帕替尼组、卡非佐米组、奥西替尼组及空白组,其差异具有统计学意义。雷帕霉素组的肿瘤个体的生长速度显著低于化疗组和空白对照组。通过进一步对肿瘤重量的结果进行分析,发现其变化趋势与肿瘤体积所表现出的结果基本一致,雷帕霉素组的肿瘤重量显著低于其他组,其抑瘤率为:72.01%。除此以外,所有实验组小鼠的体重均>23g,且未出现异常降低的情况(参见图7),说明入选实验的药物剂量在小鼠体内无明显的毒副作用。
由上述结果可以明确,mTOR通路抑制剂在体内、外均能对阴茎癌细胞产生显著的生长抑制作用,而作为对照,NCCN所提供的用于阴茎癌的一线治疗方案建议药物(顺铂+紫杉醇)在实验过程中并未体现出明确的治疗作用,同时相对于其他药物例如RTK抑制剂、蛋白酶体抑制剂具有更为显著的阴茎癌抑制效果。由此确定了mTOR抑制剂在治疗阴茎癌方面的机制及功能。对于此,本发明为阴茎癌,尤其是晚期阴茎癌提供了一种新的靶向治疗方案,能够有效扩大阴茎癌的用药谱,改善阴茎癌治疗方案单一的现状。本发明对于改善阴茎癌的预后有重要作用,具有十分重要的临床意义和社会意义。
以上具体实施方式部分对本发明所涉及的分析方法进行了具体的介绍。应当注意的是,上述介绍仅是为了帮助本领域技术人员更好地理解本发明的方法及思路,而不是对相关内容的限制。在不脱离本发明原理的情况下,本领域技术人员还可以对本发明进行适当的调整或修改,上述调整和修改也应当属于本发明的保护范围。
Claims (10)
1.一种治疗癌症的药物组合物,其特征在于,所述药物组合物包含mTOR抑制剂。
2.根据权利要求1所述的药物组合物,其特征在于,所述癌症选自阴茎癌、肾癌、肺癌、肠癌、胃癌、食管癌、肝癌、宫颈癌、乳腺癌、白血病、恶性淋巴瘤、鼻咽癌、胰腺癌中的一种或多种。
3.根据权利要求2所述的药物组合物,其特征在于,所述癌症选自阴茎癌。
4.根据权利要求1所述的药物组合物,其特征在于,所述mTOR抑制剂选自雷帕霉素、依维莫司、替西罗莫司、Ridaforolimus、AZD-8055中的一种或多种。
5.根据权利要求1所述的药物组合物,其特征在于,所述药物组合物中还包含紫杉醇、顺铂、环磷酰胺、异环磷酰胺、蛋白酶体抑制剂、RTK抑制剂中的一种或多种。
6.根据权利要求5所述的药物组合物,其特征在于,所述RTK抑制剂选自尼洛替尼、吉非替尼、厄洛替尼、拉帕替尼、阿法替尼、达可替尼、凡德他尼、来那替尼、奥希替尼、阿帕替尼、阿西替尼中的一种或多种。
7.mTOR抑制剂在制备治疗癌症药物中的应用。
8.根据权利要求7所述的应用,所述癌症选自阴茎癌、肾癌、肺癌、肠癌、胃癌、食管癌、肝癌、宫颈癌、乳腺癌、白血病、恶性淋巴瘤、鼻咽癌、胰腺癌中的一种或多种。
9.根据权利要求8所述的应用,其特征在于,所述癌症选自阴茎癌。
10.根据权利要求7-9任一项所述的应用,其特征在于,所述mTOR抑制剂选自雷帕霉素、依维莫司、替西罗莫司、Ridaforolimus、AZD-8055中的一种或多种。
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