CN117881400A - 用于预防或治疗癌症的药物组合物 - Google Patents
用于预防或治疗癌症的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种预防、改善或治疗癌症患者,尤其是上皮间质转化(Epithelial mesenchymal transition,EMT)亚型癌症患者的方法,在谷氨酰胺酶(Glutaminase,GLS)基因或通过该基因编码的蛋白质表达水平增加的癌症患者中,当联合施用磷酸甘油酸脱氢酶(PHGDH)、丝氨酸羟甲基转移酶(SHMT)及亚甲基四氢叶酸脱氢酶2(MTHFD2)抑制剂时,1C代谢得到更有效的抑制,在复发、转移及具有抗癌剂抗药性而难以治疗的难治性癌症患者中,具有抑制癌细胞增殖的协同效果,能够非常有效地治疗癌症。进而,通过测定谷氨酰胺酶基因或通过该基因编码的蛋白质表达水平,可以从早期向每位患者提供定制治疗方法相关的信息,以提高治疗成功率。
Description
技术领域
本发明涉及一种用于预防或治疗癌症的药物组合物。
背景技术
癌症是人类需要解决的难治性疾病之一,全世界为治愈癌症而投入巨额资金进行开发,就韩国而言,癌症作为疾病死亡原因中的第一大疾病,每年约有10万人以上被确诊,约6万人以上死亡。
作为这种癌症的诱发因子的致癌物质包括吸烟、紫外线、化学物质、食物及其他环境因素,但由于其诱发原因多样化,不仅难以开发治疗剂,而且根据产生部位的不同,治疗剂的效果也各不相同。目前,用作治疗剂的物质具有大量毒性,并且不能仅选择性地去除癌细胞,因此迫切需要开发一种毒性低且有效的抗癌剂,其不仅用于癌症发生后的治疗,还用于预防癌症的发生。尽管过去10年在诊断和治疗癌症方面得到飞速发展,但是癌症发病导致的致死率依旧很高。
尤其,胃癌是常见的恶性肿瘤之一,也是全球癌症死亡率的第三大原因。尽管在胃癌患者的治疗方面取得了很大的进展,但由于频繁复发及转移、或具有耐药性,胃癌患者的治疗至今仍存在局限性。
针对与癌症的复发、转移及耐药性相关的机制的研究正在积极进行中,其中癌症干细胞假说备受关注。据研究报告,干细胞样(stem-like)细胞的存在有助于此类细胞对肿瘤侵袭性、转移、复发及化疗的抗药性。
发明内容
发明要解决的问题
本发明的一目的在于,提供一种用于预防、改善或治疗癌症的药物组合物。
本发明的另一目的在于,提供一种提供上皮间质转化(Epithelial mesenchymaltransition,EMT)亚型癌症患者的治疗方法的信息的方法。
然而,本发明想要解决的技术问题并不限于上述提及的问题,并且本技术领域普通技术人员可从以下记载中清楚地理解未提及的其他问题。
用于解决问题的手段
在本发明的一实现例中,提供一种用于预防或治疗癌症的药物组合物。
在本发明的一具体例中,所述药物组合物作为有效成分包含:能够抑制谷氨酰胺酶(Glutaminase,GLS)基因的表达的制剂、或其药学上可接受的盐;以及能够抑制选自由磷酸甘油酸脱氢酶(Phosphoglycerate Dehydrogenase,PHGDH)基因、丝氨酸羟甲基转移酶(Serine hydroxymethyltransferase,SHMT)基因及亚甲基四氢叶酸脱氢酶2基因(Methylenetetrahydrofolate Dehydrogenase(NADP+D ependent)2,Methenyltetrahydrofolate Cyclohydrolase,MTHFD 2)组成的组中的任一基因的表达的制剂、或其药学上可接受的盐。
在本发明的另一具体例中,所述药物组合物作为有效成分包含:能够抑制通过谷氨酰胺酶(GLS)基因编码的蛋白质的功能的制剂、或其药学上可接受的盐;以及能够抑制通过选自由磷酸甘油酸脱氢酶(PHGDH)基因、丝氨酸羟甲基转移酶(SHMT)基因及亚甲基四氢叶酸脱氢酶2(MTHFD2)基因组成的组中的任一基因编码的蛋白质的功能的制剂、或其药学上可接受的盐。
本发明的所述“谷氨酰胺酶(GLS)基因”是编码k型线粒体谷氨酰胺酶(Glutaminase)的基因,其催化谷氨酰胺水解成谷氨酸盐及氨。尤其,就癌细胞而言,据报道,为获得大量能量源及脂肪酸合成所需的来源而过表达GLS基因,从而分解谷氨酰胺。从目的角度出发,由于癌症患者的GLS基因已过表达,因此本发明可具有通过能够抑制GLS基因表达或通过该基因表达编码的蛋白质的功能的制剂来抑制增殖或者不凋亡等特征,但不限于此。
本发明的所述GLS基因可以由SEQ ID No.1或SEQ ID No.2表示的碱基序列组成,但不限于此。
本发明的能够抑制通过所述GLS基因编码的蛋白质的功能的制剂可以是由以下化学式1(CAS No.1439399-58-2)或化学式2(CAS no.314045-39-1)表示的化合物,但不限于此。
[化学式1]
[化学式2]
本发明的所述“磷酸甘油酸脱氢酶(PHGDH)基因”是编码动物细胞中参与L丝氨酸合成初期阶段的酶的基因。
本发明的所述PHGDH基因可以由SEQ ID No.3表示的碱基序列组成,但不限于此。
本发明的所述“丝氨酸羟甲基转移酶(SHMT)基因”是编码催化丝氨酸和四氢叶酸可逆转化为甘氨酸和5,10-亚甲基四氢叶酸的酶的基因。
本发明的所述SHMT基因可以由SEQ ID No.4表示的碱基序列组成,但不限于此。
本发明的所述“亚甲基四氢叶酸脱氢酶2(MTHFD2)基因”是编码具有亚甲基四氢叶酸脱氢酶及亚甲基四氢叶酸环化水解酶(methenyltetrahydrofolatecycl ohydrolase)活性的酶的基因。
本发明的所述MTHFD2基因可以由SEQ ID No.5表示的碱基序列组成,但不限于此。
本发明的能够抑制通过所述PHGDH基因编码的蛋白质的功能的制剂可以是由以下化学式3(CAS No.1916571-90-8)表示的化合物,但不限于此。
[化学式3]
本发明的能够抑制通过所述MTHFD2基因编码的蛋白质的功能的制剂可以是由以下化学式4(CAS No.2227149-22-4)表示的化合物,但不限于此。
[化学式4]
本发明的能够抑制通过所述SHMT基因编码的蛋白质的功能的制剂可以是由以下化学式5(CAS No.2146095-85-2)表示的化合物,但不限于此。
[化学式5]
就本发明的目的而言,所述PHGDH、SHMT及MTHFD2基因以及通过该基因编码的蛋白质在癌症患者中与GLS基因及通过该基因编码的蛋白质一起表达增加,因此在与能够抑制GLS基因表达或通过该基因表达编码的蛋白质的功能的制剂一起联合用药时,可在癌症患者的癌细胞增殖抑制及凋亡方面发挥显著的协同效果。
本发明的所述“药学上可接受的盐”是指本领域技术人员通常认为适用于医学的盐(例如,因为这种盐对可用所述盐治疗的受试者无害),或者在各个治疗过程中引起可接受的副作用的盐。通常,所述药学上可接受的盐是被如美国食品药品监督管理局(FDA)、欧洲药品管理局(EMA)、或日本厚生劳动省药品医疗器械管理局(PMDA)的监管机构认为可接受的盐。
对于本发明的所述药物组合物而言,在各种情况下,本领域技术人员可容易确定本发明的特定化合物或具有生理学上作用性的其衍生物是否可形成盐,也就是说,可容易确定相当于所述本发明的抑制剂的物质或具有生理学上作用性的其衍生物是否具有如氨基、羧酸基等的带电荷的基团。
当本发明的所述能够抑制的制剂为化合物时,化合物的示例性的盐是酸加成盐或碱盐,尤其是药学上可接受的无机酸及有机酸加成盐以及药学上常用的碱盐,并且其为水不溶性或尤其是水溶性酸加成盐。根据所述化合物的取代基,碱盐也可能是适合的。例如,酸加成盐可通过混合本发明的化合物的溶液与药学上可接受的酸(如盐酸、硫酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、柠檬酸、酒石酸、碳酸或磷酸)的溶液来形成。同理,药学上可接受的碱加成盐可包含:碱金属盐(如钠盐或钾盐);碱土金属盐(如钙盐或镁盐);以及用合适的有机配体形成的盐(如使用抗衡阴离子形成的铵(如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、烷基磺酸盐及芳基磺酸盐)、季铵以及胺阳离子)。作为药学上可接受的盐的示例性实例包含乙酸盐、己二酸盐、藻酸盐、精氨酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、依地酸钙、樟脑酸盐、樟脑磺酸盐、右旋樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二葡萄糖酸盐、二盐酸盐、十二烷基硫酸盐、依地酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、半乳酸盐、半乳糖醛酸盐、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、己基间苯二酚酸盐(hexylresorcinate)、氢溴酸盐、盐酸盐、氢碘酸盐、2-羟基-乙磺酸盐、羟基萘甲酸盐、碘酸盐、异丁酸盐、羟乙基磺酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐(甲磺酸酯)、硫酸甲酯、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、泛酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐/二磷酸盐、邻苯二甲酸盐、苦味酸盐、新戊酸盐、聚半乳糖醛酸盐、丙酸盐、水杨酸盐、硬脂酸盐、硫酸盐、辛二酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、十一烷酸盐、戊酸盐等,但不限于此。
本发明的所述能够抑制基因表达的制剂可选自由化合物、与所述基因的mRNA特异性结合的miRNA、siRNA、shRNA及反义寡核苷酸组成的组中的任一种,但不限于此。
本发明的所述能够抑制蛋白质的功能的制剂可选自由化合物、反向激动剂(Inverse agonist)、拮抗剂(antagonist)及能够与所述蛋白质特异性结合的抗体或适配体组成的组中的任一种,但不限于此。
本发明的所述“反向激动剂(Inverse agonist)”或“拮抗剂(antagonist)”是指可直接或间接降低受体的生物活性的分子,并且可包括在与受体的配体一起使用时可减少所述配体的作用的分子,但不限于此。
本发明的所述“抗体”是指可与蛋白质或肽分子的抗原位点特异性结合的蛋白质分子,这种抗体可以将各基因按照常规方法克隆到表达载体中,以获得通过所述标记基因编码的蛋白质,并且通过常规方法从所获得的蛋白质中制备。
本发明的所述“适配体”是指具有规定的靶标分子的结合活性的核酸分子。所述适配体可以是RNA、DNA、修饰(modified)核酸或它们的混合物,并且可以是直链或环状形态,然而已知大致上构成所述适配体的核苷酸序列越短,其化学合成及大量生产更加容易,具有优异的成本优势,并且易于化学修饰,具有优异的体内稳定性,毒性低。
本发明的所述癌症可选自由胃癌、甲状腺癌、甲状旁腺癌、卵巢癌、大肠癌、胰腺癌、肝癌、乳腺癌、宫颈癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、非霍奇金癌淋巴瘤、霍奇金淋巴瘤、血癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头部癌、子宫癌、直肠癌、脑肿瘤、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNScentral nervoussystem)肿瘤、原发性中枢神经系统淋巴瘤、脊髓肿瘤、脑干胶质瘤及垂体腺瘤组成的组中的任一种,例如,可以是胃癌,但不限于此。
本发明的所述癌症可以是转移、复发及具有抗药性的癌症的难治性癌症,但不限于此。
本发明的所述癌症可以是上皮间质转化(Epithelial mesenchymal transition,EMT)亚型,但不限于此。
本发明的所述“EMT分子亚型”作为存在上皮细胞转变为间充质细胞的过程的亚型,是失去上皮细胞的形状并具有间充质细胞的特征的变异过程,已知是在个体形成发展中的重要过程,并且其是指可引起癌细胞的生长、抗药性、浸润及转移的分子亚型。
本发明的所述组合物还可包含抗癌剂。
本发明的所述抗癌剂可使用选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、厄洛替尼、诺拉替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、司马沙尼、波舒替尼、阿昔替尼、西地尼布、来舒替尼、曲妥珠单抗、易瑞沙、硼替佐米、舒尼替尼、卡铂、索拉非尼、贝伐单抗、顺铂、西妥昔单抗、白果槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗、替伊莫单抗、依铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、丙卡巴肼、前列地尔、硝酸钬壳聚糖、吉西他滨、多西氟尿啶、培美曲塞、替加氟、卡培他滨、吉美拉西、奥替拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、卡培他滨、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春碱、替尼泊苷、多柔比星、伊达比星、表柔比星、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡柔比星、阿柔比星、培洛霉素、替西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、立可林、特雷托宁(tretonin)、依斯美坦、氨鲁米特、阿那格雷、奥拉帕尼、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏罗唑、比卡鲁胺、洛莫司汀、伏立诺他、恩替诺特、苯乙双胍、二甲双胍、他拉佐帕尼及卡莫斯汀组成的组中的一种以上,但不限于此。
本发明的所述“预防”是指抑制或延迟疾病或病症发病的所有行为。就本发明的目的而言,所述组合物是指延迟癌症(尤其是EMT分子亚型癌症)的发病时期或者抑制发病。
本发明的所述“治疗”是指延迟、中断或逆转疾病或病症的进展的所有行为,就本发明的目的而言,是指所述组合物能够中断、减轻、缓解或消除或者逆转癌症,尤其是EMT分子亚型癌症的进展。
本发明的所述药物组合物的特征在于,可以是胶囊剂、片剂、颗粒、注射剂、软膏剂、粉末或饮料的形态,并且所述药物组合物的特征在于,可以是以人类为对象。
本发明的所述药物组合物不限于这些,而可根据各自的常规方法配制成口服剂型(如散剂、颗粒剂、胶囊剂、片剂及水混悬液)、外用剂、栓剂及无菌注射液的形态来使用。本发明的药物组合物可包含药学上可接受的载体。在口服给药时,所述药学上可接受的载体可使用粘合剂、滑泽剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素及香料等,在所述药学上可接受的载体为注射剂时,可通过混合缓冲剂、保存剂、止痛剂、增溶剂、等渗剂及稳定剂等来使用,并且在局部给药时,可使用基剂、赋形剂、润滑剂及保存剂等。
本发明的所述药物组合物的剂型可通过将其与如上所述的药学上可接受的载体混合以多种方式制备。例如,在口服给药时,可制备成片剂、锭剂(troche)、胶囊、酏剂(Elixir)、混悬剂、糖浆剂、糯米纸囊剂等,并且在其为注射剂时,可制备成单位用药安瓶或多次用药形态。另外,可配制成溶液、混悬液、片剂、胶囊、缓释制剂等。
适合本发明的所述制剂化的载体、赋形剂及稀释剂的实例可使用乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁或矿物油等。另外,还可包含填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂及防腐剂等。
本发明的所述药物组合物的给药途径可包括口服、静脉内、肌内、动脉内、髓内、鞘膜内、心脏内、经皮、皮下、腹腔内、鼻腔内、肠内、局部、舌下或直肠给药,但不限于此。优选为口服或肠胃外给药。在本发明中,所述“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、滑膜囊内、胸骨内、鞘膜内、病灶内及颅内注射或注入技术。另外,所述药物组合物可以以用于直肠给药的栓剂的形态给药。
本发明的所述药物组合物可根据多种因素而变化,所述因素包括所使用的特定化合物的活性、年龄、体重、普通健康状况、性别、饮食、给药时间、给药途径、排泄率、药物配合及预防或者待治疗特定疾病的严重程度,所述药物组合物的给药量可根据患者的状态、体重、疾病程度、药物形态、给药途径及期间而不同,但可由本领域普通技术人员进行适当地选择,并且每天可给药0.0001mg/kg至50mg/kg或0.001mg/kg至50mg/kg。给药可以每天给药一次,或者也可以分多次给药。所述给药量不以任何方式限制本发明的范围。本发明的药物组合物可配制成丸剂、糖衣剂、胶囊、液剂、凝胶剂、糖浆剂、浆剂及混悬剂。
在本发明的另一实现例中,提供一种癌症的预防、改善或治疗方法,所述方法包括:向需要给药的受试者给药药学有效剂量的组合物的步骤,所述组合物作为有效成分包含:能够抑制GLS(Glutaminase)基因的表达的制剂或其药学上可接受的盐;以及能够抑制选自由PHGDH(Phosphoglycerate Dehydrogenase)基因、SHMT(Serinehydroxymethyltransferase)基因及MTHFD2基因(Methylene tetrahydrofolateDehydrogenase(NADP+Dependent)2,Methenyltetrahydrofolate Cyclohydrolase)组成的组中的任一基因的表达的制剂或其药学上可接受的盐。
在本发明的所述癌症的预防或治疗方法中,GLS、PHGDH、SHMT或MTHFD2基因、能够抑制基因表达的制剂、药学上可接受的盐及癌症相关内容与在所述用于预防、改善或治疗癌症的组合物中记载的相同,因此将进行省略,以避免本说明书过于复杂。
在本发明中,所述“给药”是指通过任何合适的方法向受试者提供规定的本发明的组合物。
在本发明中,所述需要给药的“受试者”均可包括哺乳动物及非哺乳动物。其中,所述哺乳动物的实例可包括人类、非人类灵长类(如黑猩猩、其他猿类或猴类);畜产动物(如牛、马、羊、山羊及猪);饲养动物(如兔子、狗或猫);实验动物(如啮齿类,例如大鼠、小鼠或豚鼠等),但不限于此。另外,在本发明中,所述非哺乳动物的实例可包括鸟类或鱼类等,但不限于此。
在本发明中,以如上所述的方式给药的制剂没有特别限制,并且可以以固体形态的制剂、液体形态的制剂或吸入用气溶胶制剂给药,并且还可以以在使用之前可转变为用于口服或肠胃外给药的液体形态制剂的固体形态制剂给药,例如,可通过配制成口服剂型(散剂、颗粒剂、胶囊剂、片剂、水混悬液等)、外用剂、栓剂及无菌注射液的形态来给药,但不限于此。
另外,在本发明中,在所述给药时,可将药学上可接受的载体与本发明的制剂一起额外给药。其中,在口服给药的情况下,所述药学上可接受的载体可使用粘合剂、滑泽剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素及香料等,在注射剂的情况下,所述药学上可接受的载体可通过混合缓冲剂、保存剂、止痛剂、增溶剂、等渗剂及稳定剂等来使用,在局部给药的情况下,可使用基剂、赋形剂、润滑剂及保存剂等。本发明的化合物的剂型可通过将其与如上所述的药学上可接受的载体混合以多种方式制备。例如,在口服给药的情况下,可制备成片剂、锭剂、胶囊、酏剂(Elixir)、混悬剂、糖浆剂、糯米纸囊剂等,并且在注射剂的情况下,可制备成单位用药安瓶或多次用药形态。另外,可配制成溶液、混悬液、片剂、胶囊、缓释制剂等。
另一方面,适合本发明的所述制剂化的载体、赋形剂及稀释剂的实例可使用乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁或矿物油等。另外,还可包含填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂及防腐剂等。
本发明的制剂的给药途径不限于这些,而是包括口服、静脉内、肌内、动脉内、髓内、鞘膜内、心脏内、经皮、皮下、腹腔内、鼻腔内、肠内、局部、舌下或直肠给药。优选口服或肠胃外给药。
在本发明中,“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、滑膜囊内、胸骨内、鞘膜内、病灶内及颅内注射或注入技术。本发明的药物组合物还可以以用于直肠给药的栓剂的形态给药。
在本发明中,“药学有效剂量”是指用于提供优选生物学结果的激动剂的足够的量。所述结果可以是疾病的体征、症状或者原因的减少和/或缓解、或者生物系统中的任何其他优选的变化。例如,用于治疗用途的“有效剂量”是提供临床上显著的疾病减少所需的本发明中公开的制剂的量。在任何个别情况下,本领域普通技术人员可使用常规实验来确定适当的“有效”剂量。因此,表述“有效剂量”通常是指活性物质具有治疗效果的量。在本发明的情况下,活性物质既是癌细胞的生长抑制剂,还是癌症的预防、改善或治疗剂。
本发明的制剂可根据多种因素而具有多种变化,所述因素包括活性、年龄、体重、普通健康状况、性别、饮食、给药时间、给药途径、排泄率、药物配合及预防或者待治疗特定疾病的严重程度,所述制剂的给药量可根据患者的状态、体重、疾病程度、药物形态、给药途径及期间而不同,但可由本领域普通技术人员进行适当地选择,并且每天可给药0.0001mg/kg至100mg/kg或0.001mg/kg至100mg/kg。给药可以每天给药一次,或者也可以分多次给药。所述给药量不以任何方式限制本发明的范围。本发明的化合物可配制成丸剂、糖衣剂、胶囊、液剂、凝胶剂、糖浆剂、浆剂及混悬剂。
本发明的制剂可单独使用或者与手术、放射疗法、激素疗法、化学疗法及使用生物反应调节剂的方法联合使用。
另外,本发明的制剂也可与其他抗癌剂联合使用,此时,所述抗癌剂可使用选自由氮芥、伊马替尼、奥沙利铂、利妥昔单抗、帕尼单抗、厄洛替尼、诺拉替尼、拉帕替尼、吉非替尼、凡德他尼、尼洛替尼、司马沙尼、波舒替尼、阿昔替尼、西地尼布、来舒替尼、曲妥珠单抗、易瑞沙、硼替佐米、舒尼替尼、卡铂、5-氟尿嘧啶(5-FU)、贝伐单抗、顺铂、西妥昔单抗、阿柏西普、瑞戈非尼、白果槲寄生、天冬酰胺酶、维甲酸、羟基脲、达沙替尼、雌莫司汀、吉妥珠单抗、替伊莫单抗、依铂、甲基氨基乙酰丙酸、安吖啶、阿仑单抗、丙卡巴肼、前列地尔、硝酸钬壳聚糖、吉西他滨、多西氟尿啶、培美曲塞、替加氟、卡培他滨、吉美拉西、奥替拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、地西他滨、巯基嘌呤、硫鸟嘌呤、克拉屈滨、亚叶酸、卡莫氟、雷替曲塞、干扰素α-2a、多西他赛、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春碱、替尼泊苷、多柔比星、伊达比星、表柔比星、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素、吡柔比星、阿柔比星、培洛霉素、替西罗莫司、替莫唑胺、5-氟尿嘧啶、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、塞替派、尼莫司汀、苯丁酸氮芥、二溴卫矛醇、立可林、特雷托宁、依斯美坦、氨鲁米特、阿那格雷、诺维本、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏罗唑、比卡鲁胺、洛莫司汀及卡莫斯汀组成的组中的一种以上,但不限于此。
在本发明的另一实现例中,提供一种对EMT分子亚型癌症患者的治疗方法提供信息的方法。
本发明的所述方法包括如下的步骤:从目标个体中分离的生物学样品中,测定GLS基因或通过该基因编码的蛋白质表达水平;以及当所述经测定的基因或蛋白质表达水平增加时,判断联合用药能够抑制以下基因表达的制剂或者能够抑制通过以下基因编码的蛋白质的功能的制剂:所述基因包括:PHGDH(Phospho glycerate Dehydrogenase)基因、SHMT(Serine hydroxymethyltransferase)基因以及MTHFD2基因(MethylenetetrahydrofolateDehydrogenase(NADP+Dependen t)2,Methenyltetrahydrofolate Cyclohydrolase)。
在本发明中,所述“目标个体”是基于能够抑制GLS基因表达的制剂或者能够抑制通过该基因编码的蛋白质的功能的制剂的治疗反应性不确定的个体,其是指癌症发病、或者具有高癌症发病可能性的个体。
本发明的所述“生物学样品”是指从个体中获得或来源于个体的任何物质、生物体液、组织、或者细胞,例如,可包括全血(whole blood)、白细胞(leukocytes)、外周血单核细胞(peripheral blood mononuclear cells)、血沉棕黄层(buffy coat)、包含血浆(plasma)及血清(serum)的)血液、痰(sputum)、眼泪(tears)、粘液(mucus)、洗鼻液(nasalwashes)、鼻腔抽吸物(nasal aspirate)、呼吸(breath)、尿液(urine)、精液(semen)、唾液(saliva)、腹腔冲洗液(peritoneal washings)、盆腔积液(pelvic fluids)、囊液(cysticfluid)、脑膜液(meningeal fluid)、羊水(amniotic fluid)、腺液(glandular fluid)、胰液(pancreatic fluid)、淋巴液(lymph fluid)、胸膜液(pleural fluid)、乳头抽吸物(nipple aspirate)、支气管抽吸物(bronchial aspirate)、滑液(synovial fluid)、关节抽吸物(joint aspirate)、器官分泌物(organ secretions)、细胞(cell)、细胞提取物(cell extract)或脑脊液(cerebrospinal fluid),但不限于此。
本发明的测定所述蛋白质表达水平的方法可选自由蛋白质芯片分析、免疫测定法、配体结合分析、基质辅助激光解吸电离飞行时间质谱(Matrix Assisted L aserDesorption/Ionization Time of Flight Mass Spectrometry,MALDI-TOF)分析、表面增强激光解吸电离飞行时间质谱技术(Sulface Enhanced Laser Desorpt ion/IonizationTime of Flight Mass Spectrometry,SELDI-TOF)分析、放射免疫学分析、放射免疫扩散法、奥克特洛尼免疫扩散法、火箭免疫电泳、组织免疫染色、补体固定分析法、二维电泳分析、液相色谱-质谱(liquid chromatography-M ass Spectrometry,LC-MS)、液相色谱-质谱/质谱(liquid chromatography-Mass Spectrometry/Mass Spectrometry,LC-MS/MS)、蛋白免疫印迹及酶联免疫吸附试验(enzyme linked immunosorbentassay,ELISA)组成的组中的至少一种。
本发明的所述蛋白质表达水平可使用可测定蛋白质表达水平的制剂来测定。可测定所述蛋白质表达水平的制剂可选自由与所述蛋白质特异性结合的抗体、寡肽、配体、肽核酸(Peptide nucleic acid,PNA)及适配体(aptamer)组成的组中的至少一种。
本发明的所述“抗体”是指通过与抗原特异性结合来引起抗原-抗体反应的物质。就本发明的目的而言,抗体是指与所述蛋白质特异性结合的抗体。本发明的抗体包含多克隆抗体、单克隆抗体及重组抗体。所述抗体可使用本技术领域已知的技术而容易地制备。例如,多克隆抗体可通过本技术领域已知的方法来生产,所述方法包括:向动物注射所述蛋白质的抗原,并从动物采血以获得包含抗体的血清的步骤。这种多克隆抗体可以以任何动物制备,如山羊、兔、羊、猴、马、猪、牛、狗等。另外,单克隆抗体可通过本技术领域已知的杂交瘤方法(参见hybridoma method;Kohler及Milstein(1976)European Journal ofImmunology6:511-519)、或者噬菌体抗体库技术(参见Clackson et al,Nature,352:624-628,1991;Marks et al,J.Mol.Biol.,222:58,1-597,1991)来制备。通过所述方法制备的抗体可利用凝胶电泳、透析、盐沉淀、离子交换层析、亲和层析等方法来进行分离并纯化。另外,本发明的抗体不仅包括具有两条全长轻链及两条全长重链的完整形态,还包括抗体的功能片段。
本发明的所述抗体的功能片段是指,至少具有抗原结合功能的片段,并且具有Fab、F(ab')、F(ab')2及Fv等。
本发明的所述“肽核酸(Peptide nucleic acid,PNA)”是指与人工合成的与DNA或RNA类似的聚合物,于1991年由丹麦哥本哈根大学的Nielsen、Egholm、Berg和Buchardt教授首次提出。DNA具有磷酸核糖主链,而PNA具有通过肽键连接的重复N-(2-氨基乙基)-甘氨酸主链,由此,对DNA或RNA的结合力和稳定性大大增加,使其用于分子生物学、诊断分析及反义治疗中。
本发明的所述“适配体”是指寡核酸或肽分子。
本发明的能够测定所述蛋白质表达水平的制剂可由本领域普通技术人员基于构成本发明的所述蛋白质的氨基酸序列而容易地进行制备,具体地,所述制剂对应于与所述蛋白质特异性结合的抗体、PNA及适配体等。
本发明的测定所述基因表达水平的方法可选自由逆转录聚合酶反应(RT-PCR)、竞争性逆转录聚合酶反应(Competitive RT-PCR)、实时逆转录聚合酶反应(Real-time RT-PCR)、核糖核酸酶保护试验(RNase protection assay,RPA)、诺瑟印迹杂交(Northernblotting)及DNA芯片组成的组中的至少一种。
本发明的所述基因表达水平可使用能够测定基因表达水平的制剂来测定。能够测定所述基因表达水平的制剂可选自由与所述基因互补结合的引物、探针及反义核苷酸组成的组中的至少一种。
本发明的所述“引物”是识别靶标基因序列的片段,包括正向引物对及反向引物对,但优选为提供具有特异性及敏感性的分析结果的引物对。由于引物的核算序列是与样品中存在的非靶标序列不一致的序列,因而当仅扩增含互补引物结合位点的靶标基因序列,不诱发非特异性扩增的引物时,可赋予高特异性。
本发明的所述“探针”是指可与样品中待检测的靶标物质互补结合的物质,并且可通过所述结合特异性确认样品中靶标物质的存在的物质。探针的种类作为本技术领域通常使用的物质,并不受限,但优选地,可以为PNA(peptide nucleic acid)、锁核酸(lockednucleic acid,LNA)、肽、多肽、蛋白质、RNA或DNA,最优选地,其是PNA。更具体地,所述探针包括来源于生物或与其类似的或者在体外制备的生物材料,例如,可以是酶、蛋白质、抗体、微生物、动植物细胞及器官、神经细胞、DNA及RNA,并且DNA包含cDNA、基因组DNA、寡核苷酸,RNA包括基因组RNA、mRNA、寡核苷酸。
本发明的所述“锁核酸(locked nucleic acid,LNA)”是指包含2'-O、4'-C亚甲基桥的核酸类似物[J Weiler,J Hunziker and J Hall Gene Therapy(2006)13,496.502]。LNA核苷包含DNA和RNA的常规核酸碱基,并且可根据华森-克里克(Watson-Crick)碱基对规则来形成碱基对。然而,由于亚甲基桥导致分子“锁定(locking)”,LNA并未在华森-克里克结合中形成理想的形状。当LNA包含在DNA或RNA寡核苷酸中时,LNA可更快地与互补核苷酸链进行配对并提高双螺旋的稳定性。
本发明的所述“反义核苷酸”是指反义寡聚物通过华森-克里克碱基对的形成与RNA中的靶标序列杂交,典型地,在靶标序列中允许与mRNA形成RNA寡聚物(oligomer)异源双链体,且具有核苷酸碱基序列与亚基之间的主链的寡聚物。寡聚物可具有靶标序列的准确序列互补性或近似互补性。
本发明的能够测定所述基因表达水平的制剂可由本领域普通技术人员基于本发明的所述基因的碱基序列而容易的制备,所述制剂是对应于与所述基因互补结合的引物、探针等。
发明效果
本发明涉及一种预防、改善或治疗癌症患者的病症的方法,尤其是上皮间质转化(Epithelial mesenchymal transition,EMT)亚型癌症患者,在谷氨酰胺酶(Glutaminase,GLS)基因或通过该基因编码的蛋白质表达水平增加的癌症患者中,当联合施用磷酸甘油酸脱氢酶(PHGDH)、丝氨酸羟甲基转移酶(SHMT)及亚甲基四氢叶酸脱氢酶2(MTHFD2)抑制剂时,1C代谢得到更有效的抑制,在复发、转移及具有抗癌剂抗药性而难以治疗的难治性癌症患者中,具有抑制癌细胞增殖的协同效果,能够非常有效地治疗癌症。
进而,通过测定谷氨酰胺酶基因或通过该基因编码的蛋白质表达水平,可以从早期向每位患者提供定制治疗方法相关的信息,以提高治疗成功率。
附图说明
图1是示出在本发明一实施例的延世(Yonsei)队列胃癌患者中进行胃转录体分析的结果。
图2是示出在本发明一实施例的肠亚型细胞系(NCIN87及SNU601)及干细胞样(stem-like)亚型细胞系(MKN1及HS746T)中通过蛋白免疫印迹分析确认GLS(Glutaminase)基因编码的蛋白质表达水平的结果。
图3是示出在本发明一实施例的肠亚型类器官(organoid)(GA326)及干细胞样亚型类器官(GA077)中进行基因组分析的结果。
图4至图7分别示出乳腺癌结果:即示出了本发明一实施例确认根据是否存在谷氨酰胺(图4)以及根据作为谷氨酰胺类似物的DON的浓度的细胞系的增殖水平的结果(图5),并且,示出了确认根据作为GLS抑制剂的CB839(图6)及BPTES(图7)的浓度的细胞系的增殖水平的结果。
图8是示出通过作为本发明一实施例的GLS抑制剂的CB839单独处理来确认干细胞样亚型类器官的尺寸变化的结果。
图9至图11是示出本发明一实施例确认根据是否存在谷氨酰胺以及通过PHGD(图9)、SHMT(图10)或MTFHD2(图11)抑制剂的联合处理的干细胞样亚型细胞系的增殖水平的结果。
图12是示出确认通过本发明一实施例的GLS抑制剂(CB839)及NCT504的联合处理的干细胞样亚型类器官的尺寸变化的结果。
具体实施方式
在本发明的一实现例中,涉及一种用于预防或治疗癌症的药物组合物,其作为有效成分包含:能够抑制GLS(Glutaminase)基因的表达的制剂或其药学上可接受的盐;以及能够抑制选自由PHGDH(Phosphoglycerate Dehydrogenase)基因、SHMT(Serinehydroxymethyltransferase)基因及MTHFD2基因(Methylene tetrahydrofolateDehydrogenase(NADP+Dependent)2,Methenyltetrahydrofolate Cyclohydrolase)组成的组中的任一基因的表达的制剂或其药学上可接受的盐。
在本发明的另一实现例中,涉及一种癌症的预防、改善或治疗方法,所述方法包括:向需要给药的受试者给药药学有效剂量的组合物的步骤,其中,所述组合物作为有效成分包含:能够抑制GLS(Glutaminase)基因的表达的制剂或其药学上可接受的盐;以及能够抑制选自由PHGDH(Phosphoglycerate Dehydrogena se)基因、SHMT(Serinehydroxymethyltransferase)基因及MTHFD2基因(Met hylenetetrahydrofolateDehydrogenase(NADP+Dependent)2,Methenyltetrahydro folate Cyclohydrolase)组成的组中的任一基因的表达的制剂或其药学上可接受的盐。
在本发明的又一实现例中,涉及一种对EMT分子亚型癌症患者的治疗方法提供信息的方法,所述方法包括如下的步骤:从目标个体中分离的生物学样品中,测定GLS基因或通过该基因编码的蛋白质表达水平;以及当所述经测定的基因或蛋白质表达水平增加时,判断联合施用如下制剂,所述制剂为能够抑制以下基因表达的制剂或能够抑制通过以下基因编码的蛋白质的功能的制剂。
以下,通过以下实施例详细说明本发明。然而,以下实施例仅用于例示本发明,本发明的内容并不限于以下实施例。
实施例
[实施例1]胃转录体分析
从韩国延世癌症中心接受根治性胃切除术(curative intent gastrectomy)的胃癌患者中获得新鲜的冷冻肿瘤组织后,通过匹配临床数据的过程来获得上述转录体分析数据。本研究的所有实验经韩国延世大学医学院审查委员会(Institutional Review Board,IRB)的批准后进行,并且所述样品经患者的书面同意后进行收集。胃癌患者根据临床验证的分类体系分类为5种下游亚型(胃型(gastric)、炎症型(inflammatory)、肠型(intestinal)、混合型(mixed)及干细胞样型(难治性,stem-like,EMT分子亚型),根据常规方法,用热图(heatmap)分析与糖酵解(glycolysis)和谷氨酰胺分解过程(glutaminolysis)相关的基因,并将结果示出在图1中。
如图1所示,在延世队列胃癌患者(Yonsei cohort gastric patients)中进行转录体分析的结果表明,如热图所示,在胃癌亚型患者中,尤其在分类为干细胞样(stem-like)亚型(EMT分子亚型)的患者中,GLS(Glutaminase)基因表达水平增加。
[实施例2]在胃癌细胞系中GLS基因及蛋白质表达水平的确认
为了确认GLS基因及蛋白质表达水平,从韩国细胞系库种购买了NCIN87、SNU601、MKN1及HS746T细胞系。其中,所述NCIN87及SNU601细胞系是代表肠亚型的细胞系,MKN1及HS746T细胞系是代表干细胞样亚型的细胞系。对于所购买的细胞系,使用RPMI1640(包含10%的胎牛血清(FBS)、2mML的谷氨酰胺、100U/ml的青霉素及100μg/ml的链霉素)或DMEM(包含10%的FBS、2mML的谷氨酰胺、100U/ml的青霉素及100μg/ml的链霉素),并在37℃及5%的CO2培养箱中培养。此时,所述细胞系均经过微等离子体污染检测后,在确认没有微等离子体的污染后用于实验。将包含蛋白酶抑制剂混合液(genedepot)的EBC200(200mM的NaCl、50mM的三(羟甲基)氨基甲烷盐酸盐(Tris-HCl)(pH8.0)、0.5%的乙基苯基聚乙二醇(NP-40))放入培养的各个细胞系中,并且进行了细胞溶解过程。然后,从溶解的细胞中分离蛋白质后,通过蛋白质定量(BCA)分析方法(刺穿(Pierce)),对蛋白质的量进行定量,将等量的蛋白质上样至聚丙烯酰胺凝胶电泳(SDS-PAGE)后,进行电泳,将所述SDS-PAGE转移至聚偏二氟乙烯(PVDF)膜(Biorad公司)。在转移完成的膜上加入5%的脱脂牛奶(BD difco公司),在常温条件下进行1小时封闭(blocking)过程,然后加入与稀释成1:2000的GLS蛋白质特异性结合的抗体(abcam)及稀释成1:5000的β肌动蛋白,在4℃的温度条件下培养1天。然后,加入稀释在5%的脱脂牛奶中的二抗培养1小时后,使用LAS 4000迷你(富士胶片(Fujifilm))来确认蛋白质表达水平,并将结果示出在图2中。
如图2所示,相对于作为与肠亚型对应的细胞系的NCIN87及SNU601细胞系,在作为与干细胞样亚型对应的细胞系的MKN1及HS746T细胞系中,确认到通过GLS基因编码的蛋白质表达水平显著增加。
通过所述结果可知,相对于胃癌的其他亚型,尤其在干细胞样亚型中,通过GLS基因编码的蛋白质表达水平增加。
[实施例3]患者来源类器官的基因组分析结果
患者来源组织经韩国延世大学医学院审查委员会(Institutional ReviewBoard,IRB)的批准后获得。然后,使用所述患者来源组织,制备了与肠亚型对应的GA326类器官及与干细胞样亚型对应的GA077类器官。
具体地,在获取根据临床验证的分类体系分类为肠亚型或干细胞样亚型的患者组织后,使用包含40%的高级达尔伯克氏改良伊格尔氏培养基F12(advanced DMEM/F12)(吉布科公司(gibco))、50%的Wnt3A细胞培养液(条件培养基(conditioned media))、10%的R-spond1细胞培养液(conditioned media)、1%的4-羟乙基哌嗪乙磺酸(HEPES)(gibco)、1%的GlutaMax(gibco)、0.2%的primocin抗生素(Invivogen公司)、2%的B-27(Invitrogen)、10mM的烟酰胺(Nicotinamide)(西格玛公司(sigma))、1mM的N-乙酰半胱氨酸(N-Acetylcysteine(sigma))、2μM的A8301、50ng/ml的小鼠表皮生长因子(mEGF)(Invitrogen)、100ng/ml的重组小鼠头蛋白(mNoggin)(佩普罗科技公司(peprotech))、1nM的胃泌激素(Gastrin)(sigma)、200ng/ml的人成纤维细胞生长因子10(hFGF10)(peprotech公司)及12.5μM的Y-27632(Enzo公司)的培养基,通过使用基底胶(康宁公司(corning))来形成3D结构的过程,制备了类器官。
为了在所述各个类器官中进行转录体分析,将获得的基因组分析数据标准化为转录本拷贝数(TPM),将确认作为与GLS基因和一碳代谢相关的基因的MTR、SHMT1、SHMT2、MTHFD1及MTHFD2的转录体表达值示出在图3中。
如图3所示,相对于与肠亚型对应的GA326类器官,在与干细胞样亚型对应的GA077类器官中,确认到GLS基因表达水平显著增加。
通过所述结果可知,不仅在细胞系中,在与患者相似度高的类器官中,与其他胃癌亚型相比,GLS基因表达水平在干细胞样亚型中显著增加。
[实施例4]基于GLS抑制剂的干细胞样亚型细胞系的细胞增殖的确认
将作为肠亚型细胞系的NCIN87及作为干细胞样亚型细胞系的HS746T细胞系分别接种5000个细胞到96孔板(黑色)中,并在第二天更换为谷氨酰胺缺陷培养基(Gibco)。然后,对上述细胞系处理DON(1μM、50μM、150μM;塞莱克化学公司(selleckchem),catno.S8620)、CB839(1μM、5μM、25μM;开曼公司(cayman),cat no.S7655)或BPTES(5μM、10μM、25μM;MCE公司,cat no.HY-12683),并将处理时间设为0小时,在24小时、28小时及72小时时丢弃细胞培养基,然后保存于-80℃的超低温冷库中。在常温条件下充分培养以这种方式保存的细胞后,将200μL的含GR染料(dye)(包括在细胞存活率分析试剂盒(CyQUANT cellproliferation assay,Invitrogen)中)的细胞溶解液加入到所述培养的细胞的各孔中,并在常温条件下培养5分钟。然后,使用荧光光度计(赛默飞(thermo),多功能酶标仪varioskan flash 3001),在480nm的激发(excitation)波长及520nm的发射(emission)波长下测定荧光强度,将测定的值标准化为0小时时的细胞数,并数值化为%,将其值示出在图4至图7中。
如图4所示,就作为肠亚型细胞系的NCIN87而言,相对于包含谷氨酰胺的培养基(Gln+),在不包含谷氨酰胺的培养基(Gln-)中细胞增殖显著减少,相反地,就作为干细胞样亚型细胞系的HS746T而言,细胞增殖未随着是否包含谷氨酰胺而减少。
如图5至图7所示,就作为肠亚型细胞系的NCIN87而言,通过谷氨酰胺类似物(DON)和GLS活性抑制剂(CB839及BPTES),细胞增殖得到抑制,相反地,就作为干细胞样细胞系的HS746T而言,即使使用所述药物也未减少细胞增殖。
通过所述结果可知,就干细胞样亚型,即,难治性癌症而言,细胞增殖不受谷氨酰胺缺乏或GLS活性抑制剂的抑制。
[实施例5]确认基于GLS抑制剂的类器官中的增殖是否减少
对所述实施例3中制备的GA077类器官分别用5μM的CB839(cayman,cat no.S7655)进行处理,并将处理时间点设为D0,在1天(D1)、2天(D2)、3天(D3)及4天(D4)时通过光学显微镜(奥林巴斯(Olympus))拍摄,并且使用Image J来测定穿过中心的最长直径和最短直径,并对两个值进行平均化来测定类器官的直径。就对照组(veh;DMSO处理组)而言,重复了5次实验,就CB839处理组而言,重复6次实验。以这种方式测定的类器官的直径通过显微镜标尺换算成μm,以第0天的直径为基准进行平均化,并以%表示,将其值示出在图8中。
如图8所示,就作为干细胞样亚型的GA077类器官而言,尺寸并未通过与GLS活性抑制剂对应的CB839而减小。
通过所述结果可知,就干细胞样亚型,即难治性癌症而言,细胞增殖未受GLS活性抑制剂的抑制。
[实施例6]确认基于联合治疗的干细胞样亚型细胞系中的增殖是否减少
如所述实施例4中所示,在接种及培养作为干细胞样亚型细胞系的HS746T后,将培养基更换为谷氨酰胺缺陷培养基,给药PHGDH抑制剂(25μM)、SHMT抑制剂(1μM)或MTHFD2抑制剂(0.5μM),并将使用细胞存活率分析试剂盒测定的存活率示出在图9至图11中。
如图9至图11所示,与单独用谷氨酰胺缺乏(Gln(-)/Veh)及单独用各个抑制剂处理时(Gln(+)/PHGDHi、Gln(+)/SHMTi及Gln(+)/MTHFD2i)相比,当谷氨酰胺缺乏时以及联合施用PHGDH、SHMT或MTHFD2抑制剂(Gln(-)/PHGDHi、Gln(-)/SHMTi、Gln(-)/MTHFD2i)时,确认到作为干细胞样亚型细胞系的HS746T的存活率抑制具有显著的协同效果。
通过所述结果表明,就谷氨酰胺缺乏及对GLS抑制剂具有抗药性的干细胞样亚型,即难治性癌症而言,当分别联合施用PHGDH、SHMT及MTHFD2抑制剂时,可有效地抑制细胞的存活率。
[实施例7]确认基于联合治疗的干细胞样亚型类器官中的增殖是否减少
如所述实施例5中所示,对作为干细胞样亚型类器官的GA077分别用GLS抑制剂(CB839,5μM)、PHGDH抑制剂(NCT503,50μM)或它们的组合(combi)进行处理,并将类器官直径的平均值示出在图12中。
如图12所示,与对作为干细胞样亚型类器官的GA077分别单独用GLS抑制剂(CB839)或PHGDH抑制剂(NCT503)进行处理的情况相比,当联合用药(combi)时,类器官直径的平均值显著减小。
通过所述结果可知,就谷氨酰胺缺乏及对GLS抑制剂具有抗药性的干细胞样亚型(即难治性癌症)而言,当分别联合施用PHGDH、SHMT及MTHFD2抑制剂时,能够非常有效地减小肿瘤的大小。
以上,详细记载了本发明的特定部分,对于本技术领域普通技术人员来说显而易见的是,这种具体的记载仅为优选实现例,并不用于限制本发明的范围。因此,本发明的实质范围由所附的权利要求及其等同物来定义。
工业实用性
本发明的组合物不仅可抑制癌细胞的增殖,而且在复发、转移及具有抗癌剂抗药性而难以治疗的难治性癌症患者中,具有抑制癌细胞增殖的协同效果,能够非常有效地治疗癌症。
序列表目录(Free Text)
SEQ ID No.1:GLS
atgatgcggc tgcgaggctc ggggatgctg cgggacctgc tcctgcggtc gcccgccggcgtgagcgcga ctctgcggcg ggcacagccc ttggtcaccc tgtgccggcg tccccgaggc gggggacggccggccgcggg cccggctgcc gccgcgcgac tccacccgtg gtggggcggg ggcggctggc cggcggagcccctcgcgcgg ggcctgtcca gctctccttc ggagatcttg caggagctgg gcaaggggag cacgcatccgcagcccgggg tgtcgccacc cgctgccccg gcggcgcccg gccccaagga cggccccggg gagacggacgcgtttggcaa cagcgagggc aaagagctgg tggcctcagg tgaaaataaa ataaaacagg gtctgttacctagcttggaa gatttgctgt tctatacaat tgctgaagga caagagaaaa tacctgttca taaatttattacagcactca aatctacagg attgcgaacg tctgatccca ggttgaaaga gtgtatggat atgttaagattaactcttca aacaacatca gatggtgtca tgctagacaa agatcttttt aaaaaatgtg ttcagagcaacattgttttg ttgacacaag catttagaag aaagtttgtg attcctgact ttatgtcttt tacctcacacattgatgagt tatatgaaag tgctaaaaag cagtctggag gaaaggttgc agattatatt cctcaactggccaaattcag tcccgatttg tggggtgtgt ctgtttgtac agtagatgga cagaggcatt ctactggagataccaaagtt cccttctgtc ttcagtcctg tgtaaaacct ttgaaatatg ccattgctgt taatgatcttggaactgaat atgtgcatcg atatgttgga aaagagccga gtggactaag attcaacaaa ctatttttgaatgaagatga taaaccacat aatcctatgg taaatgctgg agcaattgtt gtgacttcac taataaagcaaggagtaaat aatgctgaaa aatttgacta tgtcatgcag tttttgaata agatggctgg taatgaatatgttggattca gtaatgcaac gtttcagtct gaaagagaaa gtggagatcg aaattttgca ataggatattacttaaaaga aaagaagtgt tttccagaag gcacagacat ggttggtata ttagacttct acttccagctgtgctccatt gaagtgactt gtgaatcagc cagtgtgatg gctgcgacac tggctaatgg tggtttctgcccaattactg gtgaaagagt actgagccct gaagcagttc gaaatacatt gagtttgatg cattcctgtggcatgtatga cttctcaggg cagtttgctt tccatgttgg tcttcctgca aaatctggag ttgctgggggcattctttta gttgtcccca atgttatggg tatgatgtgc tggtctcctc ctctggataa gatgggcaacagtgttaagg gaattcactt ttgtcacgat cttgtttctc tgtgtaattt ccataactat gataatttgagacactttgc aaaaaaactt gatcctcgaa gagaaggtgg tgatcaaagg gtaaagtcag tgataaatcttttgtttgct gcatatactg gagatgtgtc tgcacttcga agatttgctt tgtcagctat ggacatggaacagcgggact atgattctag aacagcactc catgtagctg ctgcagaggg tcatgttgaa gttgttaaatttttgctgga agcctgcaaa gtaaaccctt tccccaagga caggtggaat aacactccca tggatgaagcactgcacttt ggacaccatg atgtatttaa aattctccaa gaataccaag tccagtacac acctcaaggagattctgaca acgggaagga aaatcaaacc gtccataaga atcttgatgg attgttgtaa
SEQ ID No.2:GLS
atgatgcggc tgcgaggctc ggggatgctg cgggacctgc tcctgcggtc gcccgccggcgtgagcgcga ctctgcggcg ggcacagccc ttggtcaccc tgtgccggcg tccccgaggc gggggacggccggccgcggg cccggctgcc gccgcgcgac tccacccgtg gtggggcggg ggcggctggc cggcggagcccctcgcgcgg ggcctgtcca gctctccttc ggagatcttg caggagctgg gcaaggggag cacgcatccgcagcccgggg tgtcgccacc cgctgccccg gcggcgcccg gccccaagga cggccccggg gagacggacgcgtttggcaa cagcgagggc aaagagctgg tggcctcagg tgaaaataaa ataaaacagg gtctgttacctagcttggaa gatttgctgt tctatacaat tgctgaagga caagagaaaa tacctgttca taaatttattacagcactca aatctacagg attgcgaacg tctgatccca ggttgaaaga gtgtatggat atgttaagattaactcttca aacaacatca gatggtgtca tgctagacaa agatcttttt aaaaaatgtg ttcagagcaacattgttttg ttgacacaag catttagaag aaagtttgtg attcctgact ttatgtcttt tacctcacacattgatgagt tatatgaaag tgctaaaaag cagtctggag gaaaggttgc agattatatt cctcaactggccaaattcag tcccgatttg tggggtgtgt ctgtttgtac agtagatgga cagaggcatt ctactggagataccaaagtt cccttctgtc ttcagtcctg tgtaaaacct ttgaaatatg ccattgctgt taatgatcttggaactgaat atgtgcatcg atatgttgga aaagagccga gtggactaag attcaacaaa ctatttttgaatgaagatga taaaccacat aatcctatgg taaatgctgg agcaattgtt gtgacttcac taataaagcaaggagtaaat aatgctgaaa aatttgacta tgtcatgcag tttttgaata agatggctgg taatgaatatgttggattca gtaatgcaac gtttcagtct gaaagagaaa gtggagatcg aaattttgca ataggatattacttaaaaga aaagaagtgt tttccagaag gcacagacat ggttggtata ttagacttct acttccagctgtgctccatt gaagtgactt gtgaatcagc cagtgtgatg gctgcgacac tggctaatgg tggtttctgcccaattactg gtgaaagagt actgagccct gaagcagttc gaaatacatt gagtttgatg cattcctgtggcatgtatga cttctcaggg cagtttgctt tccatgttgg tcttcctgca aaatctggag ttgctgggggcattctttta gttgtcccca atgttatggg tatgatgtgc tggtctcctc ctctggataa gatgggcaacagtgttaagg gaattcactt ttgtcacgat cttgtttctc tgtgtaattt ccataactat gataatttgagacactttgc aaaaaaactt gatcctcgaa gagaaggtgg tgatcaaagg cattcctttg gaccattggactatgaaagt ctccaacaag aacttgcttt aaaagagaca gtatggaaaa aagtgtcacc tgagtcaaatgaggacatct ctacaactgt agtatataga atggaaagtc tgggagagaa aagctaa
SEQ ID No.3:PHGDH
atgg cttttgcaaa tctgcggaaa gtgctcatca gtgacagcct ggacccttgctgccggaaga tcttgcaaga tggagggctg caggtggtgg aaaagcagaa ccttagcaaa gaggagctgatagcggagct gcaggactgt gaaggcctta ttgttcgctc tgccaccaag gtgaccgctg atgtcatcaacgcagctgag aaactccagg tggtgggcag ggctggcaca ggtgtggaca atgtggatct ggaggccgcaacaaggaagg gcatcttggt tatgaacacc cccaatggga acagcctcag tgccgcagaa ctcacttgtggaatgatcat gtgcctggcc aggcagattc cccaggcgac ggcttcgatg aaggacggca aatgggagcggaagaagttc atgggaacag agctgaatgg aaagaccctg ggaattcttg gcctgggcag gattgggagagaggtagcta cccggatgca gtcctttggg atgaagacta tagggtatga ccccatcatt tccccagaggtctcggcctc ctttggtgtt cagcagctgc ccctggagga gatctggcct ctctgtgatt tcatcactgtgcacactcct ctcctgccct ccacgacagg cttgctgaat gacaacacct ttgcccagtg caagaagggggtgcgtgtgg tgaactgtgc ccgtggaggg atcgtggacg aaggcgccct gctccgggcc ctgcagtctggccagtgtgc cggggctgca ctggacgtgt ttacggaaga gccgccacgg gaccgggcct tggtggaccatgagaatgtc atcagctgtc cccacctggg tgccagcacc aaggaggctc agagccgctg tggggaggaaattgctgttc agttcgtgga catggtgaag gggaaatctc tcacgggggt tgtgaatgcc caggcccttaccagtgcctt ctctccacac accaagcctt ggattggtct ggcagaagct ctggggacac tgatgcgagcctgggctggg tcccccaaag ggaccatcca ggtgataaca cagggaacat ccctgaagaa tgctgggaactgcctaagcc ccgcagtcat tgtcggcctc ctgaaagagg cttccaagca ggcggatgtg aacttggtgaacgctaagct gctggtgaaa gaggctggcc tcaatgtcac cacctcccac agccctgctg caccaggggagcaaggcttc ggggaatgcc tcctggccgt ggccctggca ggcgcccctt accaggctgt gggcttggtccaaggcacta cacctgtact gcaggggctc aatggagctg tcttcaggcc agaagtgcct ctccgcagggacctgcccct gctcctattc cggactcaga cctctgaccc tgcaatgctg cctaccatga ttggcctcctggcagaggca ggcgtgcggc tgctgtccta ccagacttca ctggtgtcag atggggagac ctggcacgtcatgggcatct cctccttgct gcccagcctg gaagcgtgga agcagcatgt gactgaagcc ttccagttccacttctaa
SEQ ID No.4:SHMT2
atgctgtactt ctctttgttt tgggcggctc ggcctctgca gagatgtggg cagctggtcaggatggccat tcgggctcag cacagcaacg cagcccagac tcagactggg gaagcaaaca ggggctggacaggccaggag agcctgtcgg acagtgatcc tgagatgtgg gagttgctgc agagggagaa ggacaggcagtgtcgtggcc tggagctcat tgcctcagag aacttctgca gccgagctgc gctggaggcc ctggggtcctgtctgaacaa caagtactcg gagggttatc ctggcaagag atactatggg ggagcagagg tggtggatgaaattgagctg ctgtgccagc gccgggcctt ggaagccttt gacctggatc ctgcacagtg gggagtcaatgtccagccct actccgggtc cccagccaac ctggccgtct acacagccct tctgcaacct cacgaccggatcatggggct ggacctgccc gatgggggcc atctcaccca cggctacatg tctgacgtca agcggatatcagccacgtcc atcttcttcg agtctatgcc ctataagctc aacctggcac tgactgctcg acttttccggccacggctca tcatagctgg caccagcgcc tatgctcgcc tcattgacta cgcccgcatg agagaggtgtgtgatgaagt caaagcacac ctgctggcag acatggccca catcagtggc ctggtggctg ccaaggtgattccctcgcct ttcaagcacg cggacatcgt caccaccact actcacaaga ctcttcgagg ggccaggtcagggctcatct tctaccggaa aggggtgaag gctgtggacc ccaagactgg ccgggagatc ccttacacatttgaggaccg aatcaacttt gccgtgttcc catccctgca ggggggcccc cacaatcatg ccattgctgcagtagctgtg gccctaaagc aggcctgcac ccccatgttc cgggagtact ccctgcaggt tctgaagaatgctcgggcca tggcagatgc cctgctagag cgaggctact cactggtatc aggtggtact gacaaccacctggtgctggt ggacctgcgg cccaagggcc tggatggagc tcgggctgag cgggtgctag agcttgtatccatcactgcc aacaagaaca cctgtcctgg agaccgaagt gccatcacac cgggcggcct gcggcttggggccccagcct taacttctcg acagttccgt gaggatgact tccggagagt tgtggacttt atagatgaaggggtcaacat tggcttagag gtgaagagca agactgccaa gctccaggat ttcaaatcct tcctgcttaaggactcagaa acaagtcagc gtctggccaa cctcaggcaa cgggtggagc agtttgccag ggccttccccatgcctggtt ttgatgagca ttga
SEQ ID No.5:MTHFD2
atggctgcga cttctctaat gtctgctttg gctgcccggc tgctgcagcc cgcgcacagctgctcccttc gccttcgccc tttccacctc gcggcagttc gaaatgaagc tgttgtcatt tctggaaggaaactggccca gcagatcaag caggaagtgc ggcaggaggt agaagagtgg gtggcctcag gcaacaaacggccacacctg
agtgtgatcc tggttggcga gaatcctgca agtcactcct atgtcctcaa caaaaccagggcagctgcag
ttgtgggaat caacagtgag acaattatga aaccagcttc aatttcagag gaagaattgttgaatttaat caataaactg
aataatgatg ataatgtaga tggcctcctt gttcagttgc ctcttccaga gcatattgatgagagaagga tctgcaatgc
tgtttctcca gacaaggatg ttgatggctt tcatgtaatt aatgtaggac gaatgtgtttggatcagtat tccatgttac
cggctactcc atggggtgtg tgggaaataa tcaagcgaac tggcattcca accctagggaagaatgtggt
tgtggctgga aggtcaaaaa acgttggaat gcccattgca atgttactgc acacagatggggcgcatgaa
cgtcccggag gtgatgccac tgttacaata tctcatcgat atactcccaa agagcagttgaagaaacata caattcttgc
agatattgta atatctgctg caggtattcc aaatctgatc acagcagata tgatcaaggaaggagcagca
gtcattgatg tgggaataaa tagagttcac gatcctgtaa ctgccaaacc caagttggttggagatgtgg attttgaagg
agtcagacaa aaagctgggt atatcactcc agttcctgga ggtgttggcc ccatgacagtggcaatgcta
atgaagaata ccattattgc tgcaaaaaag gtgctgaggc ttgaagagcg agaagtgctgaagtctaaag
agcttggggt agccactaat taa
<110> 延世大学校产学协力团
<120> 用于预防或治疗癌症的药物组合物
<130> POPB222403PCT
<150> KR 10-2021-0083887
<151> 2021-06-28
<160> 5
<170> KoPatentIn 3.0
<210> 1
<211> 2010
<212> RNA
<213> 智人
<400> 1
atgatgcggc tgcgaggctc ggggatgctg cgggacctgc tcctgcggtc gcccgccggc 60
gtgagcgcga ctctgcggcg ggcacagccc ttggtcaccc tgtgccggcg tccccgaggc 120
gggggacggc cggccgcggg cccggctgcc gccgcgcgac tccacccgtg gtggggcggg 180
ggcggctggc cggcggagcc cctcgcgcgg ggcctgtcca gctctccttc ggagatcttg 240
caggagctgg gcaaggggag cacgcatccg cagcccgggg tgtcgccacc cgctgccccg 300
gcggcgcccg gccccaagga cggccccggg gagacggacg cgtttggcaa cagcgagggc 360
aaagagctgg tggcctcagg tgaaaataaa ataaaacagg gtctgttacc tagcttggaa 420
gatttgctgt tctatacaat tgctgaagga caagagaaaa tacctgttca taaatttatt 480
acagcactca aatctacagg attgcgaacg tctgatccca ggttgaaaga gtgtatggat 540
atgttaagat taactcttca aacaacatca gatggtgtca tgctagacaa agatcttttt 600
aaaaaatgtg ttcagagcaa cattgttttg ttgacacaag catttagaag aaagtttgtg 660
attcctgact ttatgtcttt tacctcacac attgatgagt tatatgaaag tgctaaaaag 720
cagtctggag gaaaggttgc agattatatt cctcaactgg ccaaattcag tcccgatttg 780
tggggtgtgt ctgtttgtac agtagatgga cagaggcatt ctactggaga taccaaagtt 840
cccttctgtc ttcagtcctg tgtaaaacct ttgaaatatg ccattgctgt taatgatctt 900
ggaactgaat atgtgcatcg atatgttgga aaagagccga gtggactaag attcaacaaa 960
ctatttttga atgaagatga taaaccacat aatcctatgg taaatgctgg agcaattgtt 1020
gtgacttcac taataaagca aggagtaaat aatgctgaaa aatttgacta tgtcatgcag 1080
tttttgaata agatggctgg taatgaatat gttggattca gtaatgcaac gtttcagtct 1140
gaaagagaaa gtggagatcg aaattttgca ataggatatt acttaaaaga aaagaagtgt 1200
tttccagaag gcacagacat ggttggtata ttagacttct acttccagct gtgctccatt 1260
gaagtgactt gtgaatcagc cagtgtgatg gctgcgacac tggctaatgg tggtttctgc 1320
ccaattactg gtgaaagagt actgagccct gaagcagttc gaaatacatt gagtttgatg 1380
cattcctgtg gcatgtatga cttctcaggg cagtttgctt tccatgttgg tcttcctgca 1440
aaatctggag ttgctggggg cattctttta gttgtcccca atgttatggg tatgatgtgc 1500
tggtctcctc ctctggataa gatgggcaac agtgttaagg gaattcactt ttgtcacgat 1560
cttgtttctc tgtgtaattt ccataactat gataatttga gacactttgc aaaaaaactt 1620
gatcctcgaa gagaaggtgg tgatcaaagg gtaaagtcag tgataaatct tttgtttgct 1680
gcatatactg gagatgtgtc tgcacttcga agatttgctt tgtcagctat ggacatggaa 1740
cagcgggact atgattctag aacagcactc catgtagctg ctgcagaggg tcatgttgaa 1800
gttgttaaat ttttgctgga agcctgcaaa gtaaaccctt tccccaagga caggtggaat 1860
aacactccca tggatgaagc actgcacttt ggacaccatg atgtatttaa aattctccaa 1920
gaataccaag tccagtacac acctcaagga gattctgaca acgggaagga aaatcaaacc 1980
gtccataaga atcttgatgg attgttgtaa 2010
<210> 2
<211> 1797
<212> RNA
<213> 智人
<400> 2
atgatgcggc tgcgaggctc ggggatgctg cgggacctgc tcctgcggtc gcccgccggc 60
gtgagcgcga ctctgcggcg ggcacagccc ttggtcaccc tgtgccggcg tccccgaggc 120
gggggacggc cggccgcggg cccggctgcc gccgcgcgac tccacccgtg gtggggcggg 180
ggcggctggc cggcggagcc cctcgcgcgg ggcctgtcca gctctccttc ggagatcttg 240
caggagctgg gcaaggggag cacgcatccg cagcccgggg tgtcgccacc cgctgccccg 300
gcggcgcccg gccccaagga cggccccggg gagacggacg cgtttggcaa cagcgagggc 360
aaagagctgg tggcctcagg tgaaaataaa ataaaacagg gtctgttacc tagcttggaa 420
gatttgctgt tctatacaat tgctgaagga caagagaaaa tacctgttca taaatttatt 480
acagcactca aatctacagg attgcgaacg tctgatccca ggttgaaaga gtgtatggat 540
atgttaagat taactcttca aacaacatca gatggtgtca tgctagacaa agatcttttt 600
aaaaaatgtg ttcagagcaa cattgttttg ttgacacaag catttagaag aaagtttgtg 660
attcctgact ttatgtcttt tacctcacac attgatgagt tatatgaaag tgctaaaaag 720
cagtctggag gaaaggttgc agattatatt cctcaactgg ccaaattcag tcccgatttg 780
tggggtgtgt ctgtttgtac agtagatgga cagaggcatt ctactggaga taccaaagtt 840
cccttctgtc ttcagtcctg tgtaaaacct ttgaaatatg ccattgctgt taatgatctt 900
ggaactgaat atgtgcatcg atatgttgga aaagagccga gtggactaag attcaacaaa 960
ctatttttga atgaagatga taaaccacat aatcctatgg taaatgctgg agcaattgtt 1020
gtgacttcac taataaagca aggagtaaat aatgctgaaa aatttgacta tgtcatgcag 1080
tttttgaata agatggctgg taatgaatat gttggattca gtaatgcaac gtttcagtct 1140
gaaagagaaa gtggagatcg aaattttgca ataggatatt acttaaaaga aaagaagtgt 1200
tttccagaag gcacagacat ggttggtata ttagacttct acttccagct gtgctccatt 1260
gaagtgactt gtgaatcagc cagtgtgatg gctgcgacac tggctaatgg tggtttctgc 1320
ccaattactg gtgaaagagt actgagccct gaagcagttc gaaatacatt gagtttgatg 1380
cattcctgtg gcatgtatga cttctcaggg cagtttgctt tccatgttgg tcttcctgca 1440
aaatctggag ttgctggggg cattctttta gttgtcccca atgttatggg tatgatgtgc 1500
tggtctcctc ctctggataa gatgggcaac agtgttaagg gaattcactt ttgtcacgat 1560
cttgtttctc tgtgtaattt ccataactat gataatttga gacactttgc aaaaaaactt 1620
gatcctcgaa gagaaggtgg tgatcaaagg cattcctttg gaccattgga ctatgaaagt 1680
ctccaacaag aacttgcttt aaaagagaca gtatggaaaa aagtgtcacc tgagtcaaat 1740
gaggacatct ctacaactgt agtatataga atggaaagtc tgggagagaa aagctaa 1797
<210> 3
<211> 1602
<212> RNA
<213> 智人
<400> 3
atggcttttg caaatctgcg gaaagtgctc atcagtgaca gcctggaccc ttgctgccgg 60
aagatcttgc aagatggagg gctgcaggtg gtggaaaagc agaaccttag caaagaggag 120
ctgatagcgg agctgcagga ctgtgaaggc cttattgttc gctctgccac caaggtgacc 180
gctgatgtca tcaacgcagc tgagaaactc caggtggtgg gcagggctgg cacaggtgtg 240
gacaatgtgg atctggaggc cgcaacaagg aagggcatct tggttatgaa cacccccaat 300
gggaacagcc tcagtgccgc agaactcact tgtggaatga tcatgtgcct ggccaggcag 360
attccccagg cgacggcttc gatgaaggac ggcaaatggg agcggaagaa gttcatggga 420
acagagctga atggaaagac cctgggaatt cttggcctgg gcaggattgg gagagaggta 480
gctacccgga tgcagtcctt tgggatgaag actatagggt atgaccccat catttcccca 540
gaggtctcgg cctcctttgg tgttcagcag ctgcccctgg aggagatctg gcctctctgt 600
gatttcatca ctgtgcacac tcctctcctg ccctccacga caggcttgct gaatgacaac 660
acctttgccc agtgcaagaa gggggtgcgt gtggtgaact gtgcccgtgg agggatcgtg 720
gacgaaggcg ccctgctccg ggccctgcag tctggccagt gtgccggggc tgcactggac 780
gtgtttacgg aagagccgcc acgggaccgg gccttggtgg accatgagaa tgtcatcagc 840
tgtccccacc tgggtgccag caccaaggag gctcagagcc gctgtgggga ggaaattgct 900
gttcagttcg tggacatggt gaaggggaaa tctctcacgg gggttgtgaa tgcccaggcc 960
cttaccagtg ccttctctcc acacaccaag ccttggattg gtctggcaga agctctgggg 1020
acactgatgc gagcctgggc tgggtccccc aaagggacca tccaggtgat aacacaggga 1080
acatccctga agaatgctgg gaactgccta agccccgcag tcattgtcgg cctcctgaaa 1140
gaggcttcca agcaggcgga tgtgaacttg gtgaacgcta agctgctggt gaaagaggct 1200
ggcctcaatg tcaccacctc ccacagccct gctgcaccag gggagcaagg cttcggggaa 1260
tgcctcctgg ccgtggccct ggcaggcgcc ccttaccagg ctgtgggctt ggtccaaggc 1320
actacacctg tactgcaggg gctcaatgga gctgtcttca ggccagaagt gcctctccgc 1380
agggacctgc ccctgctcct attccggact cagacctctg accctgcaat gctgcctacc 1440
atgattggcc tcctggcaga ggcaggcgtg cggctgctgt cctaccagac ttcactggtg 1500
tcagatgggg agacctggca cgtcatgggc atctcctcct tgctgcccag cctggaagcg 1560
tggaagcagc atgtgactga agccttccag ttccacttct aa 1602
<210> 4
<211> 1485
<212> RNA
<213> 智人
<400> 4
atgctgtact tctctttgtt ttgggcggct cggcctctgc agagatgtgg gcagctggtc 60
aggatggcca ttcgggctca gcacagcaac gcagcccaga ctcagactgg ggaagcaaac 120
aggggctgga caggccagga gagcctgtcg gacagtgatc ctgagatgtg ggagttgctg 180
cagagggaga aggacaggca gtgtcgtggc ctggagctca ttgcctcaga gaacttctgc 240
agccgagctg cgctggaggc cctggggtcc tgtctgaaca acaagtactc ggagggttat 300
cctggcaaga gatactatgg gggagcagag gtggtggatg aaattgagct gctgtgccag 360
cgccgggcct tggaagcctt tgacctggat cctgcacagt ggggagtcaa tgtccagccc 420
tactccgggt ccccagccaa cctggccgtc tacacagccc ttctgcaacc tcacgaccgg 480
atcatggggc tggacctgcc cgatgggggc catctcaccc acggctacat gtctgacgtc 540
aagcggatat cagccacgtc catcttcttc gagtctatgc cctataagct caacctggca 600
ctgactgctc gacttttccg gccacggctc atcatagctg gcaccagcgc ctatgctcgc 660
ctcattgact acgcccgcat gagagaggtg tgtgatgaag tcaaagcaca cctgctggca 720
gacatggccc acatcagtgg cctggtggct gccaaggtga ttccctcgcc tttcaagcac 780
gcggacatcg tcaccaccac tactcacaag actcttcgag gggccaggtc agggctcatc 840
ttctaccgga aaggggtgaa ggctgtggac cccaagactg gccgggagat cccttacaca 900
tttgaggacc gaatcaactt tgccgtgttc ccatccctgc aggggggccc ccacaatcat 960
gccattgctg cagtagctgt ggccctaaag caggcctgca cccccatgtt ccgggagtac 1020
tccctgcagg ttctgaagaa tgctcgggcc atggcagatg ccctgctaga gcgaggctac 1080
tcactggtat caggtggtac tgacaaccac ctggtgctgg tggacctgcg gcccaagggc 1140
ctggatggag ctcgggctga gcgggtgcta gagcttgtat ccatcactgc caacaagaac 1200
acctgtcctg gagaccgaag tgccatcaca ccgggcggcc tgcggcttgg ggccccagcc 1260
ttaacttctc gacagttccg tgaggatgac ttccggagag ttgtggactt tatagatgaa 1320
ggggtcaaca ttggcttaga ggtgaagagc aagactgcca agctccagga tttcaaatcc 1380
ttcctgctta aggactcaga aacaagtcag cgtctggcca acctcaggca acgggtggag 1440
cagtttgcca gggccttccc catgcctggt tttgatgagc attga 1485
<210> 5
<211> 1053
<212> RNA
<213> 智人
<400> 5
atggctgcga cttctctaat gtctgctttg gctgcccggc tgctgcagcc cgcgcacagc 60
tgctcccttc gccttcgccc tttccacctc gcggcagttc gaaatgaagc tgttgtcatt 120
tctggaagga aactggccca gcagatcaag caggaagtgc ggcaggaggt agaagagtgg 180
gtggcctcag gcaacaaacg gccacacctg agtgtgatcc tggttggcga gaatcctgca 240
agtcactcct atgtcctcaa caaaaccagg gcagctgcag ttgtgggaat caacagtgag 300
acaattatga aaccagcttc aatttcagag gaagaattgt tgaatttaat caataaactg 360
aataatgatg ataatgtaga tggcctcctt gttcagttgc ctcttccaga gcatattgat 420
gagagaagga tctgcaatgc tgtttctcca gacaaggatg ttgatggctt tcatgtaatt 480
aatgtaggac gaatgtgttt ggatcagtat tccatgttac cggctactcc atggggtgtg 540
tgggaaataa tcaagcgaac tggcattcca accctaggga agaatgtggt tgtggctgga 600
aggtcaaaaa acgttggaat gcccattgca atgttactgc acacagatgg ggcgcatgaa 660
cgtcccggag gtgatgccac tgttacaata tctcatcgat atactcccaa agagcagttg 720
aagaaacata caattcttgc agatattgta atatctgctg caggtattcc aaatctgatc 780
acagcagata tgatcaagga aggagcagca gtcattgatg tgggaataaa tagagttcac 840
gatcctgtaa ctgccaaacc caagttggtt ggagatgtgg attttgaagg agtcagacaa 900
aaagctgggt atatcactcc agttcctgga ggtgttggcc ccatgacagt ggcaatgcta 960
atgaagaata ccattattgc tgcaaaaaag gtgctgaggc ttgaagagcg agaagtgctg 1020
aagtctaaag agcttggggt agccactaat taa 1053
Claims (11)
1.一种用于预防或治疗癌症的药物组合物,其中,
作为有效成分包含:
能够抑制谷氨酰胺酶基因的表达的制剂、或其药学上可接受的盐;以及
能够抑制选自由磷酸甘油酸脱氢酶基因、丝氨酸羟甲基转移酶基因及亚甲基四氢叶酸脱氢酶2基因组成的组中的任一基因的表达的制剂、或其药学上可接受的盐。
2.根据权利要求1所述的药物组合物,其中,
能够抑制所述基因的表达的制剂为选自由化合物、与所述基因的mRNA特异性结合的miRNA、siRNA、shRNA及反义寡核苷酸组成的组中的任一种。
3.根据权利要求1所述的药物组合物,其中,
所述组合物还包含抗癌剂。
4.根据权利要求1所述的药物组合物,其中,
所述癌症是上皮间质转化亚型。
5.根据权利要求1所述的药物组合物,其中,
所述癌症选自由胃癌、甲状腺癌、甲状旁腺癌、卵巢癌、大肠癌、胰腺癌、肝癌、乳腺癌、宫颈癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、非霍奇金癌淋巴瘤、霍奇金淋巴瘤、血癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头部癌、子宫癌、直肠癌、脑肿瘤、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、脊髓肿瘤、脑干胶质瘤及垂体腺瘤组成的组中的任一种。
6.一种用于预防或治疗癌症的药物组合物,其中,
作为有效成分包含:
能够抑制通过谷氨酰胺酶基因编码的蛋白质的功能的制剂、或其药学上可接受的盐;以及
能够抑制通过选自由磷酸甘油酸脱氢酶基因、丝氨酸羟甲基转移酶基因及亚甲基四氢叶酸脱氢酶2基因组成的组中的任一基因编码的蛋白质的功能的制剂、或其药学上可接受的盐。
7.根据权利要求6所述的药物组合物,其中,
能够抑制所述蛋白质的功能的制剂为选自由化合物、反向激动剂、拮抗剂及能够与所述蛋白质特异性结合的抗体或适配体组成的组中的任一种。
8.根据权利要求6所述的药物组合物,其中,
所述组合物还包含抗癌剂。
9.根据权利要求6所述的药物组合物,其中,
所述癌症是上皮间质转化分子亚型。
10.根据权利要求6所述的药物组合物,其中,
所述癌症选自由胃癌、甲状腺癌、甲状旁腺癌、卵巢癌、大肠癌、胰腺癌、肝癌、乳腺癌、宫颈癌、肺癌、非小细胞肺癌、前列腺癌、胆囊癌、胆道癌、非霍奇金癌淋巴瘤、霍奇金淋巴瘤、血癌、膀胱癌、肾癌、黑色素瘤、结肠癌、骨癌、皮肤癌、头部癌、子宫癌、直肠癌、脑肿瘤、肛周癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、输尿管癌、肾细胞癌、肾盂癌、中枢神经系统肿瘤、原发性中枢神经系统淋巴瘤、脊髓肿瘤、脑干胶质瘤及垂体腺瘤组成的组中的任一种。
11.一种对上皮间质转化分子亚型癌症患者的治疗方法提供信息的方法,其中,
所述方法包括以下步骤:
从目标个体中分离的生物学样品中,测定谷氨酰胺酶基因或通过该基因编码的蛋白质表达水平;以及
当所述经测定的基因或蛋白质表达水平增加时,判断联合施用如下制剂,
所述联制剂为能够抑制以下基因表达的制剂或者能够抑制通过以下基因编码的蛋白质的功能的制剂。
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