CN117942345A - 一种arv-825分子配体治疗nut癌方法 - Google Patents
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Abstract
本发明属于生物医药领域,涉及化合物ARV‑825新的医药用途,具体涉及化合物ARV‑825通过靶向BRD4显示抗BRD4‑NUT融合蛋白的抗肿瘤活性,在制备治疗NUT癌药物中的用途。本发明公开包含ARV‑825分子治疗NUT癌的方法,所述方法为将所述包含ARV‑825分子的药物施用到患者体内,其中所述方法具体包括:一级NUT癌治疗方法,二级NUT癌治疗方法,三级NUT癌治疗方法;其中所述一级NUT癌治疗方法为,静脉注射所述包含ARV‑825分子的药物不超过200ml;其中所述二级NUT癌治疗方法为,肌肉注射所述包含ARV‑825分子的药物2‑5ml;其中所述三级NUT癌治疗方法为口服所述包含ARV‑825分子的药物,其中所述包含口服ARV‑825分子的药物为4.2mg。
Description
技术领域
本发明属于生物医药领域,涉及化合物ARV-825新的医药用途,具体涉及化合物ARV-825通过靶向BRD4显示抗BRD4-NUT融合蛋白的抗肿瘤活性,在治疗NUT癌药物中的用途。
背景技术
目前BET蛋白家族成员中研究最多的时BRD4蛋白。BRD4 是一种转录和表观遗传调节因子,在癌症发展过程中起着关键作用。
BRD4功能障碍与多种癌症的发生和进展相关,包括急性髓系白血病、结肠癌、Burkitt氏淋巴瘤、乳腺癌、弥漫性大b细胞淋巴瘤、多发性骨髓瘤和卵巢癌。此外,它是染色体15和19之间的染色体易位的位置,这是侵袭性NUT癌的原因,通常表现为单个t易位,并产生新的融合癌基因BRD4-NUT。
NUTM1(也称NUT)是NUT癌家族成员1,是仅在睾丸表达的核蛋白,其功能未知。NUTM1与BRD4融合通常在鳞状细胞癌的NUT中线亚群中发现,并在软组织肿瘤中有报道,许多其他的NUTM1融合在各种其他类型的肿瘤中也有报道。BRD4-NUT由BRD4和NUTM1融合产生,导致细胞分化抑制。BRD4-NUTM1融合与NUT癌相关。NUT基因重排可能导致NUT癌(NC),这是一种鳞状细胞癌的侵袭性亚型。NC主要作用于身体中线器官。它表现为一种单胚性低分化鳞状细胞癌。BRD4-NUT融合引起的染色体易位是遗传性疾病NC最常见的原因。这种癌症的发病年龄从不等。NC几乎是致命的,而且对目前已知的治疗方法几乎完全耐药,即使是积极的化疗,诊断为NC后的典型生存期不到一年(9.5个月)。
如何提供一种治疗NUT癌的方法是现有技术中亟待解决的问题。
发明内容
鉴于现有技术存在的问题,本发明的目的在于提供化合物ARV-825新的医药用途,化合物ARV-825通过靶向BRD4显示抗BRD4-NUT融合蛋白的抗肿瘤活性,在制备治疗NUT癌药物中的用途。本发明利用ARV-825靶向BRD4-NUT,并在3T3细胞中使用BRD4-NUT融合结构检测其体内外抗肿瘤活性,为NUT癌治疗提供了潜在的治疗药物。
为实现上述目的,本发明采用以下技术方案。
本发明的一个主要优势在于提供了一种ARV-825分子配体治疗NUT癌的方法,所述方法实现了有效治疗NUT相关癌。
本发明的其它优势和特点通过下述的详细说明得以充分体现并可通过所附权利要求中特地指出的手段得以实现。
依本发明的一个方面,是实现前述目的和其他目的和优势的一种。
本发明公开包含ARV-825分子治疗NUT癌的方法,所述方法为将所述包含ARV-825分子的药物施用到患者体内,其中所述方法具体包括:
一级NUT癌治疗方法,二级NUT癌治疗方法,三级NUT癌治疗方法;
其中所述一级NUT癌治疗方法为,静脉注射所述包含ARV-825分子的药物不超过200ml;
其中所述二级NUT癌治疗方法为,肌肉注射所述包含ARV-825分子的药物2-5ml;
其中所述三级NUT癌治疗方法为口服所述包含ARV-825分子的药物,其中所述包含口服ARV-825分子的药物为4.2mg。
在一个具体的实施例中,其中所述一级NUT癌治疗方法分为低剂量静脉注射、中等剂量静脉注射、大剂量静脉注射。
在一个具体的实施例中,其中所述ARV-825分子被处理为PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物的一个配体,其中所述PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物的另一配体为结合E3连接酶的配体。
更进一步地,所述一级NUT癌治疗方法中,60kg成人单次注射的给药浓度为:4.2mg/200ml=0.021mg/ml。
更进一步地,所述二级NUT癌治疗方法中,60kg成人单次注射给药浓度为4.2mg/5ml=0.84mg/ml。
更进一步地,所述三级NUT癌治疗方法中,所述包含ARV-825分子的药物为固体剂型包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂其中任意一种。
更进一步地,所述二级NUT癌治疗方法中,所述肌肉注射的注射部位为三角肌或股外侧肌。
更进一步地,所述二级NUT癌治疗方法适用于症状较轻缓的NUT癌患者。
更进一步地,所述一级NUT癌治疗方法适用于症状较重、较急的NUT癌患者。
更近一步地,所述三级NUT癌治疗方法适用于病情较稳定的NUT癌患者。
本发明公开的治疗NUT癌的方法能够快速减轻重症急症患者的症状,持久稳定控制NUT癌患者的病情,使患者处于一个平稳的状态,减轻患者的患病痛苦。
通过对随后的描述和附图的理解,本发明进一步的目的和优势将得以充分体现。
本发明的这些和其它目的、特点和优势,通过下述的详细说明,附图和权利要求得以充分体现。
附图说明
图1是过表达BRD4-NUT促进细胞活力、增殖和迁移。其中A是CMV-BRD4-NUT 载体构建方案。B是BRD4-NUT过表达和对照转染48小时WB检测。C是3T3细胞和3T3- BRD4-NUT细胞显微镜明场下观察,比例尺为200 μm,细胞进一步在完全培养基中并在指定的时间段进行培养;D实细胞迁移(划痕试验)检测;E是细胞活力(CCK8 OD)检测,数据以均数±标准差(SD, n=3)表示(所有数据相同)。实验重复了三次,得到了相似的结果。
图2A-2G是ARV-825抑制BRD4-NUT 3T3细胞的活性。其中2A是过表达BRD4-NUT的细胞会降低细胞活力;2B是不同浓度ARV-825处理3T3细胞后细胞增殖情况;2C是不同浓度ARV-825处理后,3T3细胞在特定时间的迁移变化,比例尺为200 μm;2D是不同浓度ARV-825处理后,3T3- BRD4-NUT细胞在特定时间的迁移变化,比例尺为200 μm;2E是ARV-825处理后过表达BRD4- NUT的细胞减少了的3T3细胞的迁移;2F是ARV-825给药后伤口愈合情况;2G是WB检测分析不同浓度ARV-825处理后3T3-BRD4-NUT细胞中BRD4蛋白表达水平的。
图3A-3E是显示ARV-825治疗后的动态变化的转录组差异。其中3A是PCA分析了四组数据,输入数据集在前两个主成分上的投影。 BN, 3T3-BRD4-NUT细胞,BN+0.003, 3T3-BRD4-NUT细胞用0.003 μM ARV-825处理,BN+0.03,3T3-BRD4-NUT细胞用0.03μ m ARV-825处理;3B是RNA-seq分析BRD4-NUT3T3和对照细胞基因表达变化的火山图,蓝色标记的基因是向上变化的基因,蓝绿色表示下调的基因,黑色表示未改变的基因;3C是3T3-BRD4-NUT细胞与3T3细胞比较差异表达基因的热图,红色表示上调,蓝色表示下调;3D是关键靶点的KEGG途径富集分析(前10位),横坐标标记为途径富集倍数;3E是将ARV-825给药前后差异表达最高的基因进行细胞功能富集分析(p<0.05, |log2FC|>1);每一列代表一个不同的样本,每一行代表一个基因,一行中的颜色变化表示相对于同一种群的平均值的表达水平,红色表示上调,蓝色表示下调,白色表示基本表达水平。
图4-1至4-6是显示ARV-825给药后RNA-Seq中基因集的基因富集的GSEA图。
图5是ARV-825在BRD4-NUT3T3异种移植瘤模型中显示抗肿瘤作用。其中A是异种移植流程图,携带异种移植瘤的裸鼠分别以10 mg/kg ARV-825或对照剂腹腔注射,持续21天。数据为平均值±SEM (n = 6);B是每3天称一次小鼠体重。C是每3天记录一次肿瘤体积,计算公式为width × width × length×0.52;D是ARV-825或安慰剂处理的小鼠的异种移植瘤照片。
具体实施方式
本发明的另一个主要优势在于提供了一种配体为ARV-825分子的PROTAC药物治疗NUT癌的方法,所述方法实现了有效治疗癌,实现缓解患者的病情,延长了患者的生存时间。
更具体地,所述NUT癌具体可以是发于纵隔、头颈部等中线部位,以及发生于肺部、鼻部、胰腺、肾、软组织、髂骨、膀胱中的恶性肿瘤。
更具体地,本发明公开的治疗NUT癌中的方法为向患者施用带有ARV-825分子配体的PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物。
在一个具体的实施例中,所述包含ARV-825分子治疗NUT癌中的方法为注射所述包含ARV-825分子的药物,其中所述方法具体包括:
一级NUT癌治疗方法,二级NUT癌治疗方法,三级NUT癌治疗方法;
其中所述一级NUT癌治疗方法为,静脉注射所述包含ARV-825分子的药物不超过200ml;
其中所述二级NUT癌治疗方法为,肌肉注射所述包含ARV-825分子的药物2-5ml;
其中所述三级NUT癌治疗方法为口服所述包含ARV-825分子的药物,其中所述包含口服ARV-825分子的药物为4.2mg。
在一个具体的实施例中,其中所述ARV-825分子被处理为PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物的一个配体,其中所述PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物的另一配体为结合E3连接酶的配体。
更进一步地,所述一级NUT癌治疗方法中,由所述含有ARV-825分子的PROTAC药物制成注射用制剂,60kg成人单次注射的给药浓度为:4.2mg/200ml=0.021mg/ml。
更进一步地,所述注射用制剂为无菌注射用水性或油性混悬剂,可使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂还可为在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射用溶液剂、混悬剂或乳剂,例如在1,3-丁二醇中的溶液剂。更具体地,所述注射用制剂可选自各种油,包括石油、动物、植物或合成来源的油,例如,花生油、大豆油、矿物油、芝麻油等。更具体地,还可以选自水、盐水、葡聚糖水溶液和二醇等与血液等渗溶液的液体载体。另外,无菌不挥发性油通常用作溶剂或混悬介质。出于该目的,可使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。另外,脂肪酸例如油酸用于制备注射剂。
在一个具体的实施例中,所述一级NUT癌治疗方法中向60kg成人注射的给药浓度为:4.2mg/200ml=0.021mg/ml,所述含有ARV-825分子的PROTAC药物的给药频率为3~4周重复。
在一个具体的实施例中,其中所述一级NUT癌治疗方法还可以进一步分为低剂量静脉注射、中等剂量静脉注射、大剂量静脉注射。
更具体地,所述一级NUT癌治疗方法中,在注射浓度为60kg成人注射的给药浓度为:4.2mg/200ml=0.021mg/ml的情况下,所述低剂量静脉注射50-100ml,更具体地,所述中剂量静脉注射100-150ml,更具体地,所述大剂量静脉注射150-200ml。
在一个具体地实施例中,低剂量静脉注射,隔日或三日给药;中等剂量在第1天和第8天使用为1个周期,一般3~4周重复,可间断用药3~4个周期;大剂量给药一般每三周一次,同时注意水化,保持尿量,可用甘露醇利尿。
更进一步地,注射用制剂可例如如下灭菌:用细菌截留过滤器过滤或将灭菌剂引入到可在使用前溶解或分散在无菌水或其它无菌注射用介质中的无菌固体组合物中。
更具体地,所述一级NUT癌治疗方法针对的NUT癌肺部癌症患者症状为咳嗽,咳痰,痰中带血。更进一步地,所述肺癌患者中大咳血、失去意识压迫气管导致肺不张、呼吸困难的患者可用所述静脉注射中的大剂量注射,以便快速产生药效,缓解患者症状。
更具体地,所述一级NUT癌治疗方法针对的NUT癌鼻部癌症患者症状为鼻腔充血、肿胀、吸气不通畅、有超出平时正常量的液体、甚至可以看到大量的脓性分泌物。更进一步地,所述NUT癌鼻部癌症患者吸气不通畅呼吸困难等危及生命症状应当采取所述静脉注射中的中剂量或大剂量注射,以便快速产生药效,缓解患者症状。
更具体地,所述一级NUT癌治疗方法针对的NUT癌纵隔癌症患者症状为上腔静脉综合征,如突然或者逐渐出现呼吸困难、面部及颈部肿胀;还可有胸腔积液,出现如胸闷、喘不上气等表现应当采取所述静脉注射中的中剂量或大剂量注射,以便快速产生药效,缓解患者症状。
更具体地,所述一级NUT癌治疗方法针对的NUT癌软组织癌症患者症状为皮肤或皮下结节,颜色可呈现红色、淡红或紫红色,也可正常,触感较硬或韧。结节可与皮下组织粘连,但少有破溃。
更具体地,所述一级NUT癌治疗方法针对的NUT癌骨骼癌症患者症状为骨骼疼痛,局部肿胀,易出现病理性骨折,此外可有脊髓压迫表现,如温觉、痛觉能力下降、肢体活动受限、大小便失禁等。
更具体地,所述一级NUT癌治疗方法针对的NUT癌膀胱癌症患者症状为血尿、输尿管和肾盂的积水、胸痛、呼吸困难等。
本申请公开的一级NUT癌治疗方法通过针对上述症状的患者进行静脉输液,可以快速缓解患者当前症状。
更进一步地,所述二级NUT癌治疗方法中,60kg成人单次注射给药浓度为4.2mg/5ml=0.84mg/ml。
更进一步地,所述二级NUT癌治疗方法中可适用症状相对较缓状态的NUT癌患者。更具体地,所述症状相对较缓具体可以是低烧、失眠、焦虑、局部疼痛等症状。更进一步地,所述二级NUT癌治疗方法适用于具备咳嗽、痰中带血、疼痛、呼吸急促其中至少一种症状的NUT癌患者。
更进一步地,所述二级NUT癌治疗方法中,所述肌肉注射的注射部位为三角肌或股外侧肌。
更进一步地,所述三级NUT癌治疗方法中,所述包含ARV-825分子的药物为固体剂型包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂其中任意一种。
更进一步地,所述三级NUT癌治疗方法适用于症状十分轻缓,不影响生活的患者,通过服用本申请的药物来维持病情,更具体地,本申请公开的口服药物单次服用不得超过4.2mg。
更具体地,所述PROTAC为两端含有不同配体的化学分子,一头是结合E3连接酶的配体,另一头是结合细胞内蛋白质的配体,这两个配体再由一段linker连接起来。这样的化学分子既可以结合E3泛素连接酶,又可以结合胞内蛋白质,通过把靶向的蛋白质招募到E3泛素连接酶附近来实现靶向蛋白质的多泛素化,最后被蛋白酶体降解。PROTAC可以循环使用,不被蛋白酶体降解。在患者体内,PROTAC的靶蛋白配体和靶蛋白结合,E3泛素连接酶配体和细胞内的E3泛素连接酶的底物结合区结合,从而通过Linker把靶蛋白拉近到E3泛素连接酶旁边,实现UPS系统将靶蛋白降解。已有研究表明,使用PROTAC技术将BRD4抑制剂与配体结合的ARV-825能更有效地分解BRD4,有效地抑制肿瘤生长,并能持续地抑制。研究表明ARV-825在胰腺癌、vemurafenib耐药黑色素瘤、胆管癌、甲状腺癌、急性髓系白血病、T细胞急性淋巴细胞白血病和神经母细胞瘤中的抗肿瘤作用。
更进一步地,本申请公开的包括ARV-825分子的PROTAC药物,能够靶向结合导致NUT癌的BRD4-NUT融合蛋白,从而实现对各种NUT癌的靶向治疗。更进一步地本申请提供了三种不同的NUT癌的治疗方式,实现了依据患者的症状来选择对应的治疗方式。
更进一步地,本申请公开的三级NUT癌治疗方法适用于症状较缓或者是没有明显症状的患者,以保持患者的日常生活,治疗并延缓病情的发作。
在一个具体的实施例中,可注射用途的药物组合物包括无菌水溶液剂(水溶性的情况下)或分散剂以及用于临时制备无菌可注射溶液剂或分散剂的无菌粉末。对于静脉内施用,合适的载体包括生理盐水、抑菌水、Cremophor EL(TM)(BASF,Parsippany,N.J.)或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物必须是无菌的,并且应该是达到容易注射的程度的流体。其在制造和储存的条件下必须是稳定的,并且必须在防止诸如细菌和真菌的微生物的污染作用下保存。载体可以是含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)的溶剂或分散介质及其合适的混合物。可例如通过使用诸如卵磷脂的包衣、在分散剂的情况下通过维持所需的粒度和通过使用表面活性剂来维持适当的流动性。可通过各种抗细菌和抗真菌剂来防止微生物的作用,例如通过对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等。在许多情况下,优选在组合物中包括等渗剂,例如糖、诸如甘露糖醇、山梨糖醇的多元醇、氯化钠。可通过在组合物中包括例如单硬脂酸铝和明胶的延迟吸收的试剂来使可注射组合物的吸收延长。
更进一步地,可通过根据需要将适当溶剂中的所需量的活性化合物(例如,TEN-010)与以上列举的成分中的一种或组合掺混、接着过滤灭菌来制备无菌可注射溶液剂。一般地,通过将活性化合物掺入到含有基本分散介质的无菌媒介物和来自以上列举的那些的所需其它成分当中来制备分散剂。在用于制备无菌可注射溶液剂的无菌粉末的情况下,制备的优选方法是真空干燥和冷冻干燥,其产生活性成分的粉末加上来自其先前无菌过滤的溶液剂的任何附加的所需成分。
在一个具体的实施例中,在所述三级NUT癌治疗方法中,所述口服组合物通常包括惰性稀释剂或可食用载体。可将它们封闭在明胶胶囊中或压缩成片剂。为了口服治疗施用的目的,可将布罗莫结构域抑制剂与赋形剂掺混,并以片剂、糖锭或胶囊的形式使用。也可使用用作漱口水的流体载体制备口服组合物,其中流体载体中的化合物被口服施加并含漱和吐出或吞咽。可包括药学上相容的粘结剂和/或佐剂物质作为组合物的一部分。片剂、丸剂、胶囊、糖锭等可含有任何以下成分或类似性质的化合物:粘结剂,如微晶纤维素、黄蓍胶或明胶;赋形剂,如淀粉或乳糖,崩解剂,如藻酸、Primogel或玉米淀粉;润滑剂,如硬脂酸镁或Sterotes;助流剂,如胶体二氧化硅;甜味剂,如蔗糖或糖精;或调味剂,如薄荷、水杨酸甲酯或橙香精(orange flavoring)。
化合物ARV-825在制备治疗NUT癌药物中的应用,所述化合物ARV-825的结构式如下式所示:。
进一步地,所述化合物ARV-825通过靶向BRD4,实现治疗或预防NUT癌。
进一步地,所述化合物ARV-825通过抑制BRD4-NUT融合蛋白表达,实现治疗或预防NUT癌。
进一步地,所述的化合物ARV-825加入药学上可接受的载体和/或辅料,制成片剂、喷雾剂、颗粒剂、胶囊剂、口服液、针剂的任一种剂型。
与现有技术比,本发明的有益效果如下。
在本发明研究中,发现ARV-825在体外和体内均能快速有效地诱导BRD4-NUT蛋白降解,并抑制3T3-BRD4-NUT细胞的生长。对细胞系异位表达系统的研究极大地提高了对NUTM1融合蛋白产生的分子改变的理解,为新的靶向药物的创建提供了新的视角,为个性化治疗提供了理论支持,并指出了有前途的靶向治疗途径,促进了NUT癌的治疗进展。这些结果表明,ARV-825是治疗BRD4-NUT癌的有效方法。
实验数据及分析
质粒构建。
从VectorBuilder中合成pLV-EGFP T2A Puro-EF1A hNUTM1质粒;pcDNA3.1-CMV-BRD4 -Flag质粒购自YouBio。构建pcDNA3.1-CMV-BRD4 NUT质粒,采用PCR扩增NUT靶基因,采用正向5 ' -aaacaggtcctgccctcgagGTTACTCTGGGTCCTGGACCTG和反向5 ' -gggccctctagactcgagCTGGCTACGACGTCGTTTCTTC引物。PCR条件:95°C孵育2分钟,然后95°C孵育30秒,50°C孵育30秒,72°C孵育4分钟35个循环,72°C孵育7分钟。pcDNA3.1-CMV-BRD4-FLAG质粒用XhoI酶切。然后,从转化的DH5α细胞和单个菌落中分离质粒DNA,连接到消化产物(EasyGeno试剂盒)中,用上述引物进行测序。
细胞转染。
3T3细胞用pcDNA3.1-CMV-BRD4 NUT (3 μg)电穿孔。转染后将细胞轻轻地重悬在1.5 mL预热的DMEM培养基中。所有细胞在37℃、5% CO2培养箱中培养。第二天,培养基改为完全DMEM培养基,细胞保持原样。48小时后,应用基因素(Sigma-Aldrich)来选择稳定的细胞系。
WB检测。
6-10% SDS-PAGE凝胶用于分离整个细胞裂解物(每个通道每次处理10-20 g蛋白质),然后转移到PVDF印迹上。阻断后,应用的一、二抗体与印迹孵育,用ECL试剂盒鉴定抗体-抗原结合。
细胞活性分析。
每孔2000个细胞被三倍地接种到96孔板上,细胞生长一夜,然后在规定的时间内使用药物。按照制造商的说明,CCK-8测试被用来测量细胞活性。
划痕试验。
6孔板培养24-48小时。当细胞达到100%融合时,使用1毫升的微移液管尖端制造伤口。去除培养基并用1ml PBS洗涤细胞后,每个孔获得2ml含有化合物的完整DMEM培养基。每12小时拍摄一次照片。导出照片后使用ImageJ测量伤口大小。
RNA-Sequencing和分析。
利用promegene提供的程序(深圳)进行RNA-测序(RNA-seq)。使用TRIzol®试剂(Invitrogen)从细胞中提取总RNA。为了建立和测序文库,RNA首先被反向转录成cDNA。使用Bioconductor limma分析,差异表达基因(|log2fold change|>1 and p<0.05)被发现。(http://www.bioinformatics.com.cn/)利用基因集富集分析(GSEA)选择了多条细胞途径进行基因富集。
体内异种移植。
从中国沈阳Lanpuda, Ltd.购买了裸鼠。800万个3T3-BRD4-NUT细胞皮下植入4周龄雄性裸鼠背部(每组6个),当移植肿瘤大小达到200 mm3左右时,每天腹腔给予ARV-82510 mg/kg或对照品。当对照组肿瘤大小达到1000 mm3时,处死小鼠。每三天,用卡尺测量皮下肿瘤的大小。肿瘤体积由公式(宽×宽×长× 0.52)确定。
结果。
过表达BRD4-NUT促进3T3细胞活性。
考虑到BRD4-NUT融合蛋白是NUT癌的癌蛋白,构建了过表达BRD4-NUT的CMV-BRD4-NUT质粒来模拟NUT癌的致病基因,如图1A所示。BRD4的外显子2-11和hNUT的2-8无缝连接,模拟NC患者的BRD4-NUT融合。Western blotting结果显示,3T3细胞中BRD4-NUT过表达,如图1B所示,但3T3细胞与3T3细胞在形态上无明显差异,如图1C所示。CCK8试验显示,过表达BRD4-NUT可显著促进3T3-BRD4-NUT细胞增殖,如图1D所示。综上所述,这些结果表明本发明成功构建了过表达BRD4-NUT融合蛋白的稳定细胞系,并发现过表达BRD4-NUT可以促进3T3细胞的增殖和活性。
ARV-825抑制3T3-BRD4-NUT细胞的增殖和迁移。
用不同剂量的ARV-825 (0.001 ~ 0.1 M)处理过表达的BRD4-NUT细胞系48小时,以评估药物对细胞的作用。接受ARV-825治疗后,3T3-BRD4-NUT细胞增殖呈剂量依赖性下降,如图2A所示。在ARV-825处理后,细胞活性大幅下降,如图2B所示。即使在测试的最低浓度(0.001 μM)下,ARV-825也显示出抑制作用,如图2A所示。此外,BRD4 PROTAC药物以时间依赖性的方式抑制了3T3-BRD4-NUT细胞活性,如图2A所示。ARV-825 (0.001 ~ 0.1 μM)处理24小时后,活性开始下降,如图2B所示,表明增殖率下降。划痕试验结果显示,ARV-825(0.001-0.03 μM, 24h)显著减少迁移的3T3-BRD4-NUT细胞数量,如图2D所示。0.1 μM ARV-825能显著抑制3T3-BRD4-NUT细胞的迁移,呈现剂量依赖性,如图2D所示。ARV-825 (0.001~ 0.03 μM, 24h)对3T3细胞的迁移和增殖没有抑制作用,而0.1μM ARV-825对3T3细胞的迁移和增殖有抑制作用,说明0.1μM ARV-825对3T3细胞具有毒性,如图2C、2D和2E所示。这些结果表明,ARV-825有效地降低了3T3-BRD4-NUT细胞的活性、增殖和迁移。Westernblotting分析结果显示,ARV-825剂量依赖性地抑制了3T3-BRD4-NUT细胞中的BRD4-NUT蛋白水平,如图2G所示。
基因转录丰度的比较分析。
通过RNA-seq来研究BRD4-NUT在转录水平上的潜在机制。测试了3T3细胞、3T3-BRD4-NUT细胞、0.003 μM和0.03μMARV-825处理后的4组数据。PCA分析将四组患者分离开来。0.003 μMARV-825的低浓度处理与0.03μMARV-825聚集在一起,而不是BRD4-NUT,说明药物处理敏感,如图3A所示。由图3B可以看出,在|log2fold change|>1 and an 调整后的p<0.01的条件下,对两个过度表达BRD4-NUT的成对3T3细胞的转录组数据进行比较,103个基因上调,159个基因下调。与3T3细胞相比,这些基因在3T3- BRD4-NUT细胞中的表达水平有显著差异。对异常基因进行功能富集分析,如图3C所示。发现Rap1信号通路、小细胞肺癌、非小细胞肺癌、膀胱癌相关基因富集,提示这些通路可能与BRD4-NUT过表达相关,如图3C所示。而在加入ARV-825后,BRD4过表达引起的异常上下调基因发生了变化,在转录水平呈现出拯救趋势,如图3E所示。同样,在GSEA富集通路中,加入ARV-825后,通路变化也呈现拯救趋势,如图4-1至4-6所示。
ARV-825在异种移植瘤模型中抑制肿瘤生长 。
利用3T3-BRD4-NUT细胞,建立NUT癌移植瘤模型,观察ARV-825在体内的抗癌作用,如图5A所示。当皮下肿瘤体积达到约200 mm3时,裸鼠每天腹腔注射ARV-825,剂量为10 mg/kg。与对照组相比,ARV-825治疗组的肿瘤体积明显降低,如图5B、5C和5D所示,但体重与治疗组和对照组无明显差异,如图5B所示。这些结果表明,ARV-825可能显著减缓NUT癌肿瘤的生长。
ARV-825治疗导致了3T3-BRD4-NUT细胞中BRD4水平更显著和更持久的下降。 RNA-seq和Western blotting分析证实了ARV-825对3T3-BRD4-NUT细胞基因表达的影响。结果表明,ARV-825抑制BRD4可导致3T3-BRD4-NUT细胞中E2F、TRAFs、Wnt、Gadd 45 g、Sox 6 mRNA的改变。对NUT癌RNA-seq数据的进一步研究可能会发现新的治疗靶点和重要的信号机制。ARV-825在3T3细胞移植模型中抑制BRD4-NUT肿瘤的过表达。根据体外实验结果,ARV-825可以降低体内BRD4蛋白水平。这进一步证明了ARV-825可能有效调控BRD4-NUT关键基因调控网络。此外,研究还表明,接受ARV-825治疗的小鼠与对照组之间的体重没有统计学上的显著差异。接受ARV-825治疗的小鼠的器官没有显示出任何其他明显的负面影响。使用JQ1治疗的小鼠体重下降,脂肪生成受损,但在ARV-825治疗的器官中,除了体重外,未观察到明显的毒性作用。这些发现表明,ARV-825既安全又有效。本发明试验研究结果表明,ARV-825治疗NUT癌是一种新的治疗策略。总之,在本发明研究中,发现ARV-825在体外和体内均能快速有效地诱导BRD4-NUT蛋白降解,并抑制3T3-BRD4-NUT细胞的生长。对细胞系异位表达系统的研究极大地提高了对NUTM1融合蛋白产生的分子改变的理解,为新的靶向药物的创建提供了新的视角,为个性化治疗提供了理论支持,并指出了有前途的靶向治疗途径,促进了NUT癌的治疗进展。这些结果表明,ARV-825是治疗BRD4-NUT癌的有效方法。
综上所述,本申请公开了一种一种ARV-825分子配体治疗NUT癌方法,能够有效延长NUT癌症患者的生命,缓解NUT癌症患者的症状,使患者处于相对舒适的生命状态。
Claims (7)
1.一种ARV-825分子配体治疗NUT癌方法,其特征在于,将所述包含ARV-825分子的药物施用到患者体内,其中将所述方法具体包括:一级NUT癌治疗方法,二级NUT癌治疗方法,三级NUT癌治疗方法;
其中所述一级NUT癌治疗方法为,静脉注射所述包含ARV-825分子的药物不超过200ml;
其中所述二级NUT癌治疗方法为,肌肉注射所述包含ARV-825分子的药物2-5ml;
其中所述三级NUT癌治疗方法为口服所述包含ARV-825分子的药物,其中所述包含口服ARV-825分子的药物为4.2mg。
2.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述一级NUT癌治疗方法分为低剂量静脉注射、中等剂量静脉注射、大剂量静脉注射。
3.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述ARV-825分子被处理为PROTAC(proteolysis-targetingchimeras, 蛋白降解靶向联合体)药物的一个配体,其中所述PROTAC(proteolysis-targeting chimeras, 蛋白降解靶向联合体)药物的另一配体为结合E3连接酶的配体。
4.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述一级NUT癌治疗方法中,60kg成人单次注射的给药浓度为:4.2mg/200ml=0.021mg/ml。
5.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述二级NUT癌治疗方法中,60kg成人单次注射给药浓度为4.2mg/5ml=0.84mg/ml。
6.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述三级NUT癌治疗方法中,所述包含ARV-825分子的药物为固体剂型包括胶囊剂、片剂、丸剂、粉末剂和颗粒剂其中任意一种。
7.根据权利要求1所述的ARV-825分子配体治疗NUT癌方法,其中所述二级NUT癌治疗方法中,所述肌肉注射的注射部位为三角肌或股外侧肌。
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