CN107530340B - 治疗脑肿瘤的方法 - Google Patents
治疗脑肿瘤的方法 Download PDFInfo
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- CN107530340B CN107530340B CN201680020652.9A CN201680020652A CN107530340B CN 107530340 B CN107530340 B CN 107530340B CN 201680020652 A CN201680020652 A CN 201680020652A CN 107530340 B CN107530340 B CN 107530340B
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Abstract
本申请公开了通过施用普那布林治疗脑肿瘤的方法。一些实施方案涉及通过施用普那布林治疗多形性胶质母细胞瘤。
Description
通过引用并入任何优先权申请
本申请要求于2015年3月6日提交的美国临时申请第62/129623号和2015年11月2日提交的美国临时申请第62/249807号的权益，将其公开内容通过引用整体并入本文。
背景技术
技术领域
本发明涉及化学和医药领域。更具体地，本发明涉及使用普那布林(Plinabulin)治疗脑肿瘤的方法。
相关领域的描述
脑和神经***的癌症是最难治疗的。患有这些癌症的患者的预后取决于肿瘤的类型和位置以及其发育阶段。对于许多类型的脑癌而言，症状发作后的平均预期寿命可能为数月或一两年。治疗主要由手术切除和放射疗法组成。也使用化学疗法，但合适化疗剂的范围有限，这可能是因为大多数治疗剂不能充分穿透血脑屏障以治疗脑肿瘤。使用已知的化学疗法以及手术和放射很少将存活延长至远超过通过单独的手术放射产生的存活。因此，对于脑肿瘤而言，需要改进的治疗选择，并且这种状况具有极度未满足的医疗需求。
多形性胶质母细胞瘤(GBM)为最常见的成人原发性脑肿瘤，因其致命性和对当前治疗方法缺少响应而闻名。对于患有GBM的患者而言，近年来治疗选择没有实质性改善，并且存活前景存在最低限度的改善。对于GBM，症状发作后的平均预期寿命为大约6-12个月。另外，没有获得批准用于治疗转移性脑肿瘤的药物，所述转移性脑肿瘤在症状发作后具有4-6个月的平均预期寿命。因此，迫切需要改善对脑部癌症的治疗。
发明概述
一些实施方案涉及治疗脑肿瘤的方法，其包括向有需要的受试者施用有效量的普那布林。
一些实施方案涉及抑制脑肿瘤细胞增殖的方法，其包括使脑肿瘤细胞与普那布林接触。
一些实施方案涉及诱导脑肿瘤细胞凋亡的方法，其包括使脑肿瘤细胞与普那布林接触。
一些实施方案涉及抑制脑肿瘤进展的方法，其包括向有需要的受试者施用有效量的普那布林。
附图简述
图1a-1d显示模拟人类病理学的胶质母细胞瘤(GBM)的原神经遗传工程化鼠模型(GEMM)。图1a显示表现瘤周水肿的人GBM的T2MRI图像；图1b显示表现瘤周水肿的小鼠GBM的T2MRI图像；图1c显示示出标志性假栅栏状坏死和微血管增生的GBM的H&E染色的人显微照片图像；图1d显示示出标志性假栅栏状坏死和微血管增生的GBM的H&E染色的小鼠显微照片图像。
图2A和2B显示T2加权的MRI图像。图2A显示用媒介物、替莫唑胺(temozolomide)或分级放射处理的患有PDGF诱导的胶质瘤的小鼠中的肿瘤大小；以及图2B显示用媒介物、替莫唑胺或分级放射处理的患有PDGF诱导的胶质瘤的小鼠的存活。
图3显示用对照和普那布林治疗的具有胶质母细胞瘤肿瘤的小鼠的存活率。
图4显示用普那布林、替莫唑胺和放射的组合以及替莫唑胺和放射的组合治疗的患有由KRAS突变的表达为特征的PDGF诱导的胶质瘤的小鼠的存活率。
优选实施方案详述
普那布林，即(3Z,6Z)-3-苯亚甲基-6-{[5-(2-甲基-2-丙基)-1H-咪唑-4-基]亚甲基}-2,5-哌嗪二酮，是天然化合物Phenylahistin的合成类似物。可以根据美国专利第7,064,201号和第7,919,497号(将其通过引用整体并入本文)中详细描述的方法和步骤容易地制备普那布林。一些实施方案涉及使用普那布林治疗脑癌，包括但不限于转移性脑肿瘤、间变性星形细胞瘤、多形性胶质母细胞瘤、少突胶质细胞瘤、室管膜细胞瘤和混合的胶质瘤。一些实施方案涉及使用普那布林抑制脑肿瘤细胞的增殖。一些实施方案涉及使用普那布林诱导脑肿瘤细胞的凋亡。一些实施方案涉及使用普那布林抑制脑肿瘤的进展。一些实施方案涉及使用普那布林与另外的治疗剂或放射的组合来抑制脑肿瘤的进展。
定义
除非另有定义，否则本文使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常理解的相同的含义。所有专利、申请、公开的申请和其它出版物均通过引用整体并入本文。如果本文中有一个术语的多个定义，除非另有说明，否则以本节中的定义为准。
如本文所用，“受试者”意指人或非人哺乳动物，例如狗、猫、小鼠、大鼠、牛、绵羊、猪、山羊、非人灵长类动物或鸟(如鸡)，以及任何其它脊椎动物或无脊椎动物。
术语“哺乳动物”以其通常的生物学意义使用。因此，其具体包括但不限于：灵长类动物(包括类人猿(黑猩猩、猿、猴)和人)、牛、马、绵羊、山羊、猪、兔、狗、猫、啮齿动物、大鼠、小鼠、豚鼠等。
如本文所用，“有效量”或“治疗有效量”是指治疗剂的量，其在一定程度上有效地缓解或降低疾病或病况的一种或多种症状发作的可能性，并且包括治愈疾病或病况。
如本文所用，“治疗”(treat/treatment/treating)是指向受试者施用化合物或药物组合物以用于预防和/或治疗目的。术语“预防性治疗”是指治疗尚未表现出疾病或病况的症状但是易患或以其它方式具有特定疾病或病况风险的受试者，从而该治疗降低患者将来发展疾病或病况的可能性。术语“治疗性治疗”是指对已经罹患疾病或病况的受试者进行治疗。
术语“药学可接受的盐”是指这样的盐，其保留了化合物的生物学效应和性质，并且不是生物学上或在其它方面中不期望用于药物的盐。在许多情况下，由于氨基和/或羧基或与其相似的基团的存在，本文公开的化合物能够形成酸式盐和/或碱式盐。可以用无机酸和有机酸形成药学可接受的酸加成盐。可以衍生出盐的无机酸包括，例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生出盐的有机酸包括，例如醋酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。也可以使用无机碱和有机碱形成药学可接受的盐。可以衍生出盐的无机碱包括，例如含有钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等的碱；特别优选为铵、钾、钠、钙和镁盐。在一些实施方案中，用无机碱处理本文公开的化合物导致来自化合物的不稳定氢的丢失以提供包括无机阳离子，如Li+、Na+、K+、Mg2+和Ca2+等的盐形式。可以衍生出盐的有机碱包括，例如伯胺、仲胺和叔胺、取代的胺(包括天然产生的取代的胺)、环胺、碱离子交换树脂等，具体地例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。许多此类盐为本领域已知的，如1987年9月11日公开的Johnston等人的WO 87/05297中所述(通过引用整体并入本文)。
在一些实施方案中，组合物还可以包含一种或多种药学可接受的稀释剂。在一些实施方案中，药学可接受的稀释剂可以包括
(聚乙二醇(15)-羟基硬脂酸酯)。在一些实施方案中，药学可接受的稀释剂可以包括丙二醇。在一些实施方案中，药学可接受的稀释剂可以包括kolliphor和丙二醇。在一些实施方案中，药学可接受的稀释剂可以包括kolliphor和丙二醇，其中基于稀释剂的总重量，kolliphor为按重量计约40％，并且丙二醇为按重量计约60％。在一些实施方案中，组合物还可以包含一种或多种其它的药学可接受的赋形剂。
可以使用标准的药物制剂技术，如Remington's The Science and Practice ofPharmacy,21st Ed.,Lippincott Williams&Wilkins(2005)中公开的那些技术(将其通过引用整体并入本文)以制备本文所述的药物组合物。因此，一些实施方案包括药物组合物，其包含：(a)安全和治疗有效量的普那布林或其药学可接受的盐；以及(b)药学可接受的载体、稀释剂、赋形剂或它们的组合。
其它实施方案包括在分别的组合物或同一组合物中共同施用普那布林和另外的治疗剂。因此，一些实施方案包括第一药物组合物，其包含：(a)安全和治疗有效量的普那布林或其药学可接受的盐，以及(b)药学可接受的载体、稀释剂、赋形剂或它们的组合；以及第二药物组合物，其包含：(a)安全和治疗有效量的另外的治疗剂，以及(b)药学可接受的载体、稀释剂、赋形剂或它们的组合。一些实施方案包括药物组合物，其包含：(a)安全和治疗有效量的普那布林或其药学可接受的盐；(b)安全和治疗有效量的另外的治疗剂；以及(c)药学可接受的载体、稀释剂、赋形剂或它们的组合。
可以经由任何一种可以接受的适用于类似用途的试剂的施用模式施用本文所述的药物组合物，所述施用模式包括但不限于：口服、舌下、口腔、皮下、静脉内、鼻内、局部、经皮、皮内、腹膜内、肌内、肺内、***、直肠或眼内。在治疗适应症(其为优选实施方案的对象)中，口服和肠胃外施用是常用的。
术语“药学可接受的载体”或“药学可接受的赋形剂”包括任何和所有溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。将此类介质和试剂用于药物活性物质是本领域公知的。除了任何常规介质或试剂与活性成分不相容的情形之外，其在治疗组合物中的用途是可预期的。此外，可以包括例如本领域常用的各种佐剂。以下描述了将各种组分包含于药物组合物中的考虑，例如，Gilman等人(Eds.)(1990)；Goodman和Gilman’s:The Pharmacological Basis of Therapeutics,8th Ed.,Pergamon Press，将其通过引用整体并入本文。
可作为药学可接受的载体或其组分的物质的一些实例为：糖，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲纤维素钠、乙基纤维素和甲基纤维素；粉状黄蓍胶；麦芽；明胶；滑石；固体润滑剂，如硬脂酸和硬脂酸镁；硫酸钙；植物油，如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油；多元醇，如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇；海藻酸；乳化剂，如TWEENS；润湿剂，如十二烷基硫酸钠；着色剂；调味剂；压片剂；稳定剂；抗氧化剂；防腐剂；无热原水；等渗盐水和磷酸盐缓冲溶液。
本文所述的组合物优选以单位剂型提供。如本文所用，“单位剂型”是包含一定量的化合物或组合物的组合物，其适于根据良好医疗实践(good medical practice)，以单一剂量向动物(优选哺乳动物受试者)施用。然而，单个或单位剂型的制剂并不意味着该剂型每天施用一次或每个疗程施用一次。预期此类剂型以每天一次、两次、三次或更多次施用，并且可以以输注一段时间施用(例如，约30分钟至约2-6小时)，或作为连续输注施用，以及可以在治疗过程期间给药不止一次，尽管没有特别排除单次施用。本领域技术人员应认识到，该制剂没有具体预期整个治疗过程，并且将这些决定留给治疗领域而不是制剂领域的技术人员。
如上所述有用的组合物可以是用于多种施用途径的多种合适形式中的任何一种，例如用于口服、舌下、口腔、鼻、直肠、局部(包括透皮和皮内)、眼部、脑内、颅内、鞘内、动脉内、静脉内、肌内施用，或其它肠胃外施用途径。本领域技术人员应理解，口服和鼻用组合物包括通过吸入施用并以可用的方法制备的组合物。根据所需的特定施用途径，可以使用本领域众所周知的多种药学可接受的载体。药学可接受的载体包括例如，固体或液体填充剂、稀释剂、水溶助剂、表面活性剂和封装物质。可以包括任选的药物活性物质，其不会实质上干扰化合物或组合物的活性。与化合物或组合物结合使用的载体的量足以提供用于每单位剂量的化合物施用的材料的实际量。制备可用于本文所述方法的剂型的技术和组合物描述于以下文献(将其全部通过引用并入本文)：Modern Pharmaceutics,4th Ed.,Chapters9and 10(Banker&Rhodes,editors,2002)；Lieberman等人,Pharmaceutical DosageForms:Tablets(1989)；和Ansel,Introduction to Pharmaceutical Dosage Forms 8thEdition(2004)。
可以使用各种口服剂型，包括如片剂、胶囊(例如，液体凝胶胶囊和固体凝胶胶囊)、颗粒剂和散装粉末的固体形式。片剂可以为压缩的片剂、片剂研磨物、包有肠溶衣、糖衣、薄膜包衣的片剂或多次压缩的片剂，其含有合适的粘合剂、润滑剂、稀释剂、崩解剂、着色剂、调味剂、流动诱导剂和熔化剂(melting agent)。液体口服剂型包括水溶液、乳液、悬浮液、由非泡腾颗粒重新构成的溶液和/或悬浮液，以及由泡腾颗粒重新构成的泡腾制剂，该剂型中含有合适的溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、熔化剂、着色剂和调味剂。
适于制备经口施用的单位剂型的药学可接受的载体为本领域众所周知的。片剂通常包含作为惰性稀释剂的常规药学上相容的佐剂，如碳酸钙、碳酸钠、甘露糖醇、乳糖和纤维素；粘合剂，如淀粉、明胶和蔗糖；崩解剂，如淀粉、海藻酸和交联羧甲纤维素；润滑剂，如硬脂酸镁、硬脂酸和滑石。诸如二氧化硅的助流剂可以用于改善粉末混合物的流动特性。为了外观，可以添加着色剂，如FD&C染料。甜味剂和调味剂，如阿斯巴甜、糖精、薄荷醇、薄荷、蔗糖和水果香料是咀嚼片的有用佐剂。胶囊通常包含一种或多种上文公开的固体稀释剂。载体组分的选择取决于次要考虑因素，如味道、成本和贮存稳定性，这不是关键的并且可以由本领域技术人员容易地进行。
经口的组合物还可以包含液体溶液、乳剂、悬浮液等。适于制备此类组合物的药学可接受的载体为本领域众所周知的。用于糖浆、酏剂、乳剂和悬浮液的载体的典型组分包括乙醇、甘油、丙二醇、聚乙二醇、液体蔗糖、山梨糖醇和水。对于悬浮液，典型的悬浮剂包括甲基纤维素、羧甲基纤维素钠、AVICEL RC-591、黄蓍胶和海藻酸钠；典型的润湿剂包括卵磷脂和聚山梨醇酯80；典型的防腐剂包括对羟基苯甲酸甲酯和苯甲酸钠。经口的液体组合物还可以含有如上文公开的甜味剂、调味剂和着色剂中的一种或多种组分。
此类组合物也可以通过常规方法进行包衣，通常使用pH或时间依赖性包衣，使得主题组合物在期望的局部应用附近的胃肠道中释放，或者在不同时间释放以延长期望的作用。这种剂型通常包括但不限于乙酸邻苯二甲酸纤维素、聚乙烯乙酸邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、乙基纤维素、Eudragit包衣、蜡和虫胶中的一种或多种。
本文描述的组合物可以任选地包括其它药物活性物质。
用于实现全身递送主题化合物的其它组合物包括舌下、口腔和鼻用剂型。此类组合物通常包含一种或多种可溶性填料物质，如蔗糖、山梨糖醇和甘露糖醇；以及粘合剂，如***树胶、微晶纤维素、羧甲基纤维素和羟丙基甲基纤维素。也可以包括上文公开的助流剂、润滑剂、甜味剂、着色剂、抗氧化剂和调味剂。
配制液体组合物(将其配制为用于局部眼科应用)使得其可以局部施用于眼部。应当尽可能使舒适感最大化，但有时出于配制考虑(例如药物稳定性)可能无法达到最佳舒适感。在不能将舒适感最大化的情况下，可以将其配制成液体，使得液体对局部眼科应用的患者而言是可容忍的。另外，眼科可接受的液体可以被包装成单次使用，或含有防腐剂以预防经多次使用的污染。
对于眼科应用，通常用生理盐水溶液作为主要媒介物制备溶液或药物。可以优选用适当的缓冲***使眼科溶液保持舒适的pH。制剂还可以含有常规的药学可接受的防腐剂、稳定剂和表面活性剂。
可以用于本文公开的药物组合物的防腐剂包括但不限于苯扎氯铵、PHMB、氯丁醇、硫柳汞、醋酸苯汞和硝酸苯汞。有用的表面活性剂为例如Tween 80。同样地，多种有用的媒介物可以用于本文所公开的眼科制剂中。这些媒介物包括但不限于聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊洛沙姆(poloxamer)、羧甲基纤维素、羟乙基纤维素和纯化水。
可以根据需要或便利添加张力调节剂。它们包括但不限于盐(尤其是氯化钠、氯化钾)、甘露糖醇和甘油，或任何其它合适的眼科可接受的张力调节剂。
可以使用多种用于调节pH的缓冲液和方法，只要所得的制剂是眼科可接受的。对于许多组合物，pH为4至9。因此，缓冲液包括醋酸盐缓冲液、柠檬酸盐缓冲液、磷酸盐缓冲液和硼酸盐缓冲液。根据需要，可以用酸或碱调节这些制剂的pH。
眼科可接受的抗氧化剂包括但不限于焦亚硫酸钠、硫代硫酸钠、乙酰半胱氨酸、丁基羟基茴香醚和丁羟甲苯。
可以包含在眼科制剂中的其它赋形剂组分为螯合剂。有用的螯合剂为乙二胺四乙酸二钠(EDTA)，但是还可以用其它螯合剂代替它或与它结合。
对于局部应用，可以使用包含本文所公开的组合物的乳膏剂、软膏剂、凝胶、溶液或悬浮液等。局部制剂可以通常包括药物载体、共溶剂、乳化剂、渗透促进剂、防腐剂体系和软化剂。
对于静脉内施用，可以将本文所述的组合物溶解或分散在药学可接受的稀释剂(如盐水或葡萄糖溶液)中。还可以包含合适的赋形剂以达到期望的pH，其包括但不限于NaOH、碳酸钠、醋酸钠、HCl和柠檬酸。在多种实施方案中，最终组合物的pH为2至8，或优选4至7。抗氧化剂赋形剂可以包括亚硫酸氢钠、丙酮合亚硫酸氢钠、甲醛次硫酸氢钠、硫脲和EDTA。出现在最终的静脉内组合物中的合适的赋形剂的其它非限制性实例可以包括磷酸钠或磷酸钾、柠檬酸、酒石酸、明胶和诸如葡萄糖、甘露糖醇和葡聚糖的碳水化合物。其它可接受的赋形剂描述于Powell等人，Compendium of Excipients for ParenteralFormulations,PDA J Pharm Sci and Tech 1998,52 238-311和Nema等人，Excipientsand Their Role in Approved Injectable Products:Current Usage and FutureDirections,PDA J Pharm Sci and Tech 2011,65 287-332，这两者通过引用将其整体并入本文。还可以包含抗微生物剂以获得抑制细菌或抑制真菌的溶液，其包括但不限于硝酸苯汞、硫柳汞、苄索氯铵、苯扎氯铵、苯酚、甲酚和氯丁醇。
可以以一种或多种固体形式向护理人员提供用于静脉内施用的组合物，在施用之前可以立即用合适的稀释剂如无菌水、盐水或葡萄糖水溶液复原。在其它实施方案中，以准备好的溶液形式提供组合物以进行肠胃外施用。在其它实施方案中，以在施用之前需进一步稀释的溶液形式提供组合物。在包括施用本文所述的化合物与其它试剂的组合的实施方案中，作为混合物向护理人员提供该组合，或护理人员在施用之前混合两种试剂，或可以单独地施用两种试剂。
本文所述的活性化合物的实际剂量取决于具体化合物和待治疗的病况；适当剂量的选择是技术人员所熟知的。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约5mg/m2至约150mg/m2的体表面积、约5mg/m2至约100mg/m2的体表面积、约10mg/m2至约100mg/m2的体表面积、约10mg/m2至约80mg/m2的体表面积、约10mg/m2至约50mg/m2的体表面积、约10mg/m2至约40mg/m2的体表面积、约10mg/m2至约30mg/m2的体表面积、约13.5mg/m2至约100mg/m2的体表面积、约13.5mg/m2至约80mg/m2的体表面积、约13.5mg/m2至约50mg/m2的体表面积、约13.5mg/m2至约40mg/m2的体表面积、约13.5mg/m2至约30mg/m2的体表面积、约15mg/m2至约80mg/m2的体表面积、约15mg/m2至约50mg/m2的体表面积、或约15mg/m2至约30mg/m2的体表面积。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约13.5mg/m2至约30mg/m2的体表面积。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约5mg/m2、约10mg/m2、约12.5mg/m2、约13.5mg/m2、约15mg/m2、约17.5mg/m2、约20mg/m2、约22.5mg/m2、约25mg/m2、约27.5mg/m2、约30mg/m2、约40mg/m2、约50mg/m2、约60mg/m2、约70mg/m2、约80mg/m2、约90mg/m2、或约100mg/m2的体表面积。
在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约5mg至约300mg、约5mg至约200mg、约7.5mg至约200mg、约10mg至约100mg、约15mg至约100mg、约20mg至约100mg、约30mg至约100mg、约40mg至约100mg、约10mg至约80mg、约15mg至约80mg、约20mg至约80mg、约30mg至约80mg、约40mg至约80mg、约10mg至约60mg、约15mg至约60mg、约20mg至约60mg、约30mg至约60mg、或约40mg至约60mg。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约20mg至约60mg、约27mg至约60mg、约20mg至约45mg、或约27mg至约45mg。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以为约5mg、约10mg、约12.5mg、约13.5mg、约15mg、约17.5mg、约20mg、约22.5mg、约25mg、约27mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约125mg、约150mg或约200mg。
只要肿瘤保持在控制之下并且方案为临床上耐受的，施用周期可以为多周的治疗周期。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以每周施用一次，并且优选在三周(21天)的治疗周期的第1天和第8天各施用一次。在一些实施方案中，单个剂量的普那布林或其它治疗剂可以在一周、两周、三周、四周或五周的治疗周期内以每周一次、每周两次、每周三次、每周四次、每周五次、每周六次或每天进行施用。可以在治疗周期的每周中的同一天或不同天施用。
只要方案为临床上耐受的，就可以重复治疗周期。在一些实施方案中，重复n次治疗周期，其中n为2至30的整数。在一些实施方案中，n为2、3、4、5、6、7、8、9或10。在一些实施方案中，新的治疗周期可以在先前的治疗周期完成之后立即发生。在一些实施方案中，新的治疗周期可以在先前的治疗周期完成之后的一段时间内发生。
在一些实施方案中，本文所述的组合物可以与其它治疗剂组合使用。在一些实施方案中，本文所述的组合物可以与治疗(如化疗、放射和生物疗法)组合施用或使用。
治疗方法
一些实施方案涉及治疗脑肿瘤的方法，所述方法包括向有需要的受试者施用有效量的普那布林。
在一些实施方案中，脑肿瘤可以选自转移性脑肿瘤、间变性星形细胞瘤、多形性胶质母细胞瘤、少突胶质细胞瘤、室管膜细胞瘤、脑膜瘤、混合的胶质瘤以及它们的组合。在一些实施方案中，脑肿瘤为多形性胶质母细胞瘤。在一些实施方案中，脑肿瘤为转移性脑肿瘤。
在一些实施方案中，脑肿瘤可以选自间变性星形细胞瘤、中枢神经细胞瘤、脉络丛癌、脉络丛***状瘤、脉络丛肿瘤、胚胎发育不良性神经上皮肿瘤、室管膜肿瘤、纤维性星形细胞瘤、巨细胞胶质母细胞瘤、多形性胶质母细胞瘤、脑胶质瘤病、胶质肉瘤、血管外皮细胞瘤、成神经管细胞瘤、髓质上皮瘤、脑膜癌病、成神经细胞瘤、神经细胞瘤、少突星形细胞瘤、少突胶质细胞瘤、视神经鞘脑膜瘤、小儿室管膜瘤、毛细胞型星形细胞瘤、松果体母细胞瘤、松果体细胞瘤、多形性间变型神经母细胞瘤、多形性黄色星形细胞瘤、原发性中枢神经***淋巴瘤、蝶骨嵴脑膜瘤、室管膜下巨细胞星形细胞瘤、亚室管膜瘤、中枢神经***骨髓瘤和三侧性视网膜母细胞瘤。
在一些实施方案中，本文所述的方法可以包括施用另外的治疗剂。在一些实施方案中，另外的治疗剂可以为替莫唑胺(temozolomide)、贝伐珠单抗、依维莫司(everolimus)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、丙卡巴肼(procarbazine)、长春新碱、伊立替康(irinotecan)、顺铂、卡铂、甲氨蝶呤、依托泊苷(etoposide)、长春花碱、博来霉素、放线菌素、环磷酰胺或异环磷酰胺。在一些实施方案中，另外的治疗剂可以为替莫唑胺。在一些实施方案中，另外的治疗剂可以为洛莫司汀。
在一些实施方案中，本文所述的方法还可以包括使受试者经受放射疗法。在一些实施方案中，放射疗法可以为全脑照射、分级放射疗法和放射外科。
在一些实施方案中，脑肿瘤的特征在于KRAS的突变形式的表达。在一些实施方案中，脑肿瘤的特征在于不是KRAS的突变基因的表达。
在一些实施方案中，本文所述的方法还可以包括鉴定患有以突变型KRAS表达为特征的癌症的患者。在一些实施方案中，本文所述的方法还可以包括鉴定患有以野生型KRAS表达为特征的癌症的患者。在一些实施方案中，鉴定患者可以包括确定患者是否具有KRAS突变。一些实施方案涉及用于在被鉴定为具有KRAS突变的患者中治疗癌症的方法，所述方法包括向患者施用药学有效量的普那布林，其中已经通过以下来鉴定患者：(i)从患者收集样品；(ii)从样品分离DNA；(iii)扩增分离的DNA中的KRAS基因或其片段；和(iv)检测扩增的KRAS基因中是否存在突变，从而确定患者是否患有以KRAS突变为特征的癌症。
一些实施方案涉及抑制脑肿瘤细胞增殖的方法，所述方法包括使脑肿瘤细胞与普那布林接触。在一些实施方案中，接触包括向具有脑肿瘤细胞的受试者施用有效量的普那布林。在一些实施方案中，脑肿瘤为多形性胶质母细胞瘤。
一些实施方案涉及诱导脑肿瘤细胞凋亡的方法，所述方法包括使脑肿瘤细胞与普那布林接触。在一些实施方案中，接触包向具有脑肿瘤细胞的受试者施用有效量的普那布林。在一些实施方案中，脑肿瘤为多形性胶质母细胞瘤。
一些实施方案涉及抑制脑肿瘤进展的方法，所述方法包括向有需要的受试者施用有效量的普那布林。
为了进一步说明本发明，包括了下述实施例。该实施例当然不应被解释为具体限制本发明。在权利要求范围内的这些实施例的变化在本领域技术人员的权限范围内，并且被认为落在如本文所述和所要求保护的本发明的范围内。读者将认识到，掌握了本公开的技术人员和本领域技术人员能够准备和使用本发明而无需详尽的实例。
实施例
实施例1
使用的小鼠胶质瘤模型为PDGF驱动的胶质瘤的GEMM，其模拟胶质母细胞瘤(GBM)的原神经分子亚组。该模型基于体细胞特异性基因转移；具有复制能力的ALV剪接受体(RCAS)逆转录病毒***允许在紧密调节的分化窗口中以细胞类型特异性方式注入特定的基因改变。RCAS/tv-a***采用RCAS逆转录病毒载体来感染遗传工程化小鼠以在特定细胞群中表达RCAS受体(tv-a)。此处，通过RCAS介导的PDGF转移到脑中表达巢蛋白的细胞来产生胶质瘤。巢蛋白在脑的干细胞/祖细胞群中表达，并且已经被证明是人和小鼠脑肿瘤中位于血管周区域(PVN)的癌症干细胞的标志物。当与Ink4a-arf-/-缺失组合在感染后4-5周，PDGF驱动的胶质瘤出现完全的外显率。这些肿瘤准确模拟了GBM的“原神经”亚型，其中在56％的“原神经”人胶质瘤中，观察到CDKN2A(编码p16INK4A和p14ARF)缺失。如图1a-1d所示，在该GEMM中重现了限定人胶质瘤的肿瘤细胞结构，如Scherer结构、微血管增生和假栅栏状坏死。具体地，图1a显示表现瘤周水肿的人GBM的T2MRI图像；图1b显示表现瘤周水肿的小鼠GBM的T2MRI图像；图1c显示具有标志性假栅栏状坏死和微血管增生的GBM的H&E染色的人显微照片图像；以及图1d显示具有标志性假栅栏状坏死和微血管增生的GBM的H&E染色的小鼠显微照片图像。
胶质瘤细胞沿白质轨迹迁移，包围神经元和血管并在软膜下空间的脑部边缘积累。在这方面，PDGF驱动的胶质瘤的GEMM与PVN-GBM非常相似，并且代表了定义肿瘤微环境中的肿瘤细胞与非肿瘤细胞之间的相互作用的极好的实验体系。
如图2A和2B中所示，PDGF诱导的胶质瘤模型用于确定对放射和替莫唑胺的反应。图2A显示用媒介物、替莫唑胺或分级放射处理的患有PDGF诱导的胶质瘤的小鼠的肿瘤大小；和图2B显示用媒介物、替莫唑胺或分级放射处理的患有PDGF诱导的胶质瘤的小鼠的存活率。
通过症状鉴定患有胶质瘤的小鼠并通过T2加权的MRI验证。用媒介物、每天25mg/kg的替莫唑胺处理小鼠12天，或者以每周5天每天2Gy的剂量分级放射处理小鼠2周(共计20Gy)。图2A中的两个顶部图像显示未处理的(媒介物)的肿瘤的生长，相比之下，经替莫唑胺处理的和照射的肿瘤在同一时间段内体积缩小。如在这些相应的小鼠群组的存活曲线中可见，这些肿瘤在治疗之后复发，并且所有动物死于复发性肿瘤。数据表明：1)在该小鼠模型中进行试验，2)这些治疗对小鼠存活的影响反映了人类状况，3)所有小鼠死于疾病，和4)这些鼠群组的相对均一结果支持了使用该实验范例来检测本研究中的存活差异。
产生使用RCAS/tv-a的患有PDGF诱导的胶质瘤的小鼠。小鼠为转基因的，用于表达从巢蛋白启动子的RCAS受体(tv-a)并具有ink4a/arf-/-和lox-stop-lox荧光素酶背景，其感染有RCAS-PDGF或者RCAS-PDGF和表达G12D突变的KRAS的RCAS-KRAS的组合。对于单独的PDGF，在该背景下，所产生的肿瘤在最初4-5周出现，而由PDGF和RCAS的组合引起的肿瘤早约一周出现。肿瘤具有GBM的组织学特性，并且通过嗜眠和梳毛差的症状、使用T2加权序列的MRI扫描或用IVIS***的生物发光成像来鉴定。对于放射疗法，每天以单个剂量用10Gy于颅骨治疗小鼠。如图2B中所示，该治疗使具有GBM的小鼠群组的存活中值延长大约3周。这些经治疗的小鼠开始体重增加，在几天内显示出改善的症状，并且它们的MRI成像特征显示出肿瘤大小的稳定或缩小，然后再复发并死亡。
在患有表达G12D突变的KRAS的PDGF诱导的胶质瘤的小鼠中测试普那布林。用异氟烷麻醉4-6周龄的nestin-tv-a/ink4a-arf-/-小鼠并向其注射转染了RCAS-PDGF-B-HA、RCAS-KRAS的Df-1细胞。使用立体定向框架经由连接到汉密尔顿(Hamilton)注射器的26G(26-gauge)针向小鼠注射1微升的2X105的RCAS-PDGF-B-HA/RCAS-KRAS的1:1混合物。将细胞注射到右额皮质中，坐标为前囱1.75mm，Lat-0.5mm且深度为2mm。仔细监测小鼠的体重减轻，并在连续2天总计失去>0.3克或表现出肿瘤的外部迹象时，对所述小鼠进行研究。在KRAS组中，用7.5mg/kg普那布林i.p.注射小鼠，每周两次，持续10周。在对照组中，仅用普那布林稀释剂(40wt％的Kolliphor和60wt％的丙二醇)注射小鼠。监测小鼠的嗜眠、驼背姿势、食欲减退、肿瘤生长的外部迹象、躁动、体重减轻和总体未能茁壮成长。当小鼠失去超过20％的体重、失去可动性、不能进食或者对于雄性称重小于14克/对于雌性称重小于12克时，处死小鼠。使用CO2处死小鼠，获取脑部并将其在10％的中性缓冲***中储存过夜，然后用Flex 80代替，并储存在4度。
图3显示出患有具有G12D Kras突变的胶质母细胞瘤的小鼠的存活率。如图3中所示，与对照组相比，具有PDGF诱导的胶质母细胞瘤模型的小鼠在普那布林处理组中通常具有显著较好的存活率(p＝0.001)。
实施例2.
使用根据实施例1的方案制备患有表达G12D突变的KRAS的PDGF诱导的胶质瘤的小鼠，并将其用于本实验中。用异氟烷麻醉4-6周龄的nestin-tv-a/ink4a-arf-/-小鼠并向其注射转染了RCAS-PDGF-B-HA、RCAS-KRAS的Df-1细胞。使用立体定向框架经由连接到汉密尔顿注射器的26G针，向小鼠注射1微升的2X105的RCAS-PDGF-B-HA/RCAS-KRAS的1:1混合物。将细胞注射到右额皮质中，坐标为前囱1.75mm，Lat-0.5mm且深度为2mm。仔细监测小鼠的体重减轻，并在连续2天总计失去>0.3克或表现出肿瘤的外部迹象时，对所述小鼠进行研究。
小鼠进入两个研究组。一组小鼠用替莫唑胺(TMZ)、放射和普那布林的组合处理：以10gy x1给予放射，在每周的星期一和星期四腹膜内施用TMZ和含7.5mg/kg普那布林的普那布林稀释剂两次，持续10周。另一组，即对照组，用TMZ和放射的组合处理：以10gy x1给予放射，在每周的星期一和星期四腹膜内施用TMZ两次，持续10周。监测小鼠的嗜眠、驼背姿势、食欲减退、肿瘤生长的外部迹象、躁动、体重减轻和总体未能茁壮成长。当小鼠失去超过20％的体重、失去可动性、不能进食或对于雄性称重小于14克/对于雌性称重小于12克时，处死小鼠。使用CO2处死小鼠；获取脑部并将其在10％的中性缓冲***中储存过夜，然后用Flex 80代替，并储存在4度。如图4中所示，与接受TMZ加放射的对照组相比，具有PDGF诱导的胶质母细胞瘤模型的小鼠在普那布林加TMZ加放射治疗组中通常具有显著较好的存活率(p＝0.0149)。
Claims (6)
1.普那布林在制备用于治疗受试者的脑肿瘤的药物中的用途，其中所述脑肿瘤为多形性胶质母细胞瘤，并且所述脑肿瘤的特征在于KRAS的突变形式的表达。
2.如权利要求1所述的用途，其中所述药物还包括另外的治疗剂。
3.如权利要求2所述的用途，其中所述另外的治疗剂为替莫唑胺。
4.如权利要求1所述的用途，其中所述受试者经受放射疗法。
5.如权利要求2所述的用途，其中所述受试者经受放射疗法。
6.普那布林在制备用于抑制脑肿瘤进展的药物中的用途，其中所述脑肿瘤为多形性胶质母细胞瘤，并且脑肿瘤的特征在于KRAS的突变形式的表达。
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| CA2978679A1 (en) | 2016-09-15 |
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| AU2016229295B2 (en) | 2021-11-04 |
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| IL254262A0 (en) | 2017-10-31 |
| EP3265091A1 (en) | 2018-01-10 |
| BR112017018964A2 (pt) | 2018-05-22 |
| KR102623404B1 (ko) | 2024-01-11 |
| JP2021091695A (ja) | 2021-06-17 |
| JP7264331B2 (ja) | 2023-04-25 |
| WO2016144636A1 (en) | 2016-09-15 |
| MX2017011375A (es) | 2018-01-23 |
| HK1250007A1 (zh) | 2018-11-23 |
| CL2017002242A1 (es) | 2018-04-02 |
| ZA201706035B (en) | 2019-12-18 |
| AU2021254549A1 (en) | 2021-11-18 |
| KR20170123642A (ko) | 2017-11-08 |
| RU2017131448A (ru) | 2019-04-08 |
| SG11201707128TA (en) | 2017-09-28 |
| US10076518B2 (en) | 2018-09-18 |
| HK1249051A1 (zh) | 2018-10-26 |
| RU2728796C2 (ru) | 2020-07-31 |
| US10357491B2 (en) | 2019-07-23 |
| JP2018507245A (ja) | 2018-03-15 |
| EP3265091A4 (en) | 2018-08-01 |
| JP6904570B2 (ja) | 2021-07-21 |
| MY194341A (en) | 2022-11-29 |
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