CN104010494A - Pik3ca h1047r敲入非人动物乳腺癌模型 - Google Patents
Pik3ca h1047r敲入非人动物乳腺癌模型 Download PDFInfo
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Abstract
本发明涉及PIK3CA H1047R敲入非人动物乳腺癌模型的开发,及其用于鉴定涉及纺锤细胞肿瘤形成的自发性功能丧失性TP53突变的用途。本发明还涉及使用这种模型对乳腺肿瘤中别的体细胞突变和拷贝数异常的鉴定,及用于诊断和治疗乳腺癌的方法和手段。
Description
发明领域
本发明涉及PIK3CA H1047R敲入非人动物乳腺癌模型的开发,及其用于鉴定涉及纺锤细胞肿瘤形成的自发性功能丧失性TP53突变的用途。本发明还涉及使用这种模型对乳腺肿瘤中别的体细胞突变和拷贝数异常的鉴定,及用于诊断和治疗乳腺癌的方法和手段。
发明背景
IA类PI3K催化亚基p110α,p110β和p110δ作为与p85α,p55α,p50α,p85β或p55γ调节亚基复合的专性异二聚体存在。在正常细胞中,PI3K维持于基础无活性状态且在生长因子刺激和细胞表面受体参与后变成有活性。活化的PI3K磷酸化并转化磷脂酰肌醇4,5二磷酸酯(PIP2),产生磷脂酰肌醇3,4,5三磷酸酯(PIP3)。升高的细胞PIP3水平促进PI3K效应器活化,其继而调节多种细胞过程,包括细胞生长,增殖和存活(参见Cantley,L.C.,Science296,1655-7(2002);Hawkins,P.T.et al.,Biochem Soc Trans34,647-62(2006);及Vanhaesebroeck,B.,et al.,Trends Biochem Sci30,194-204(2005))。
已经在结肠直肠癌,乳腺癌和肝癌中报告了编码p110α的基因PIK3CA中的频繁体细胞突变(Samuels,Y.et al.,Science304,554(2004);Bachman,K.E.et al.,Cancer Biol Ther3,772-5(2004);Lee,J.W.et al.,Oncogene24,1477-1480(2004))。报告的p110α突变大多发生在三个热点中–螺旋域中的两个(E542K和E545K)和激酶域中的一个(H1047R)(Bader,A.G.et al.,Nat Rev Cancer5,921-9(2005);Zhao,L.& Vogt,P.K.,Proc Natl Acad Sci U S A105,2652-7(2008))。这些热点突变产生致癌性p110α,其能够组成性激活下游信号传导(Zhao,L.& Vogt,见上文)。而且,在异种移植物模型中,该p110α突变体在细胞中表达时能导致细胞转化及支持肿瘤形成(Samuels et al.,见上文;Zhao,L.& Vogt,Oncogene27,5486-5496(2008);Isakoff,S.J.,Cancer Research65,10992-11000(2005);Bader,A.G.,Proceedings of the National Academy of Sciences103,1475-1479(2006);Horn, S.et al.,Oncogene27,4096-4106(2008))。
人癌症的遗传工程化小鼠模型(GEMM)充当重要资源,用于了解肿瘤启动和进展(Walrath,J.C.,Hawes,J.J.,Van Dyke,T.& Reilly,K.M.,Genetically engineered mouse models in cancer research.Adv Cancer Res106,113-64(2010))。GEMM还已经用于测试治疗剂及开发治疗策略(Singh,M.et al.,Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models.Nat Biotechnol28,585-93(2010))。致力于了解突变型PIK3CA所致致癌性转化的研究主要使用基于细胞的系统,异种移植物模型和转基因模型(Samuels et al.,见上文;Isakoff,见上文;Bader,A.G.,见上文;Horn,S.et al.,见上文;Engelman,J.A.et al.,Nat Med14,1351-6(2008);Adams,J.R.et al.,Cancer Research71,2706-2717(2011);Meyer,D.S.et al.,Cancer Research(2011))。鉴于PIK3CA突变的较高频率和一直以来开发小分子抑制剂的努力,能自其天然启动子和基因组架构表达内源水平的突变型PIK3CA敲入小鼠模型将会是研究肿瘤启动,进展和治疗的有价值工具。还有,此类模型自身将会适于鉴定在肿瘤发生期间与突变型PIK3CA合作的损伤。
想着这一点,我们制备了遗传工程化小鼠模型,其中通过放置一休眠拷贝编码H1047R的致癌性突变型PIK3CA外显子20,与编码外显子20的野生型相邻,我们修饰了内源PIK3CA等位基因。在激活休眠突变型等位基因之前,工程化小鼠表达经修饰野生型PIK3CA(PIK3CAe20mwt)。然而,在Cre介导的重组之后,突变型PIK3CA H1047R等位基因PIK3CAe20H1047R被激活,导致其表达。我们显示了PIK3CA H1047R等位基因在小鼠乳腺上皮中的条件性激活导致突变型PIK3CA H1047R表达和肿瘤发生。
虽然下一代测序能够随着人肿瘤发生和发展进行人肿瘤的碱基对水平表征(Shah,S.P.et al.,Nature461,809-813(2009);Ding,L.et al.,Nature464,999-1005(2010)),癌症的小鼠模型提供确定的实验易处理系统,其容许随着肿瘤发生进行系统性采样和肿瘤表征。
在序列水平表征肿瘤的一项努力中,我们实施了肿瘤全外显子组捕捉和测序,并鉴定出自发性功能丧失性TP53突变的出现,其作为涉及纺锤细胞肿瘤形成的潜在合作事件。本发明还涉及来自这种模型的乳腺肿瘤中别的体细胞突变和拷贝数异常的鉴定。在分子表征之外,还对PI3K小分子抑制剂的能 力测试了功效,而且结果显示肿瘤响应抑制剂治疗。
发明概述
一方面,本发明涉及一种非人转基因动物,其包含经修饰内源PIK3CA基因座,其中所述经修饰内源PIK3CA基因座包含与野生型外显子20相邻的编码H1047R的休眠突变型PIK3CA外显子20,且其中所述非人转基因动物能够进行PIK3CA H1047R(PIK3CAe20H1047R)突变型等位基因的条件性表达。
在一个实施方案中,所述突变型等位基因处于PIK3CA内源启动子控制之下。
在另一个实施方案中,条件性表达是由突变型等位基因通过Cre介导的重组的激活触发的。
在还有另一个实施方案中,条件性激活是组织特异性的。
在又一个实施方案中,条件性激活导致突变型PIK3CAH1047R表达和肿瘤发生。
在所有实施方案中,所述非人转基因动物可以是例如啮齿类动物,诸如小鼠或大鼠。
另一方面,本发明涉及一种荷瘤非人转基因动物,其条件性表达PIK3CAH1047R(PIK3CAe20H1047R)突变型等位基因处于PIK3CA内源启动子控制之下。
在一个实施方案中,所述动物以组织特异性方式表达PIK3CA H1047R突变型等位基因。
在另一个实施方案中,所述PIK3CA H1047R突变型等位基因在所述动物的乳腺中表达且所述肿瘤是乳腺肿瘤。
在还有另一个实施方案中,所述荷瘤非人转基因动物对于PIK3CAH1047R突变型等位基因是杂合的。
在另一个实施方案中,所述荷瘤非人转基因动物对于PIK3CA H1047R突变型等位基因是纯合的。
在又一个实施方案中,所述乳腺肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
在还有又一个实施方案中,所述荷瘤非人转基因动物为啮齿类动物,诸如小鼠或大鼠。
又一方面,本发明涉及一种用于生成上文所述转基因动物的方法,其包 括放置一拷贝编码H1047R突变的外显子20,与编码野生型PIK3CA等位基因的外显子20相邻。
在一个实施方案中,编码野生型PIK3CA等位基因的外显子20侧翼为lexP位点,接着是转录终止盒和一拷贝编码H1047R突变的PIK3CA外显子20。
又一方面,本发明涉及一种对受试者筛选肿瘤存在情况的方法,该方法包括对自所述受试者获得的生物学样品测试PIK3CA H1047R等位基因的存在情况或相应基因产物。
在一个实施方案中,所述肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
在另一个实施方案中,所述肿瘤选自下组:乳腺癌,卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌,子宫内膜癌,白血病和中枢神经系统恶性肿瘤。
在还有另一个实施方案中,所述肿瘤为乳腺癌。
在又一个实施方案中,所述方法进一步包括对所述样品测试次要体细胞突变的存在情况或拷贝数改变,其中所述次要体细胞突变可以例如在TP53基因中,诸如R248H TP53突变。在其它实施方案中,所述次要体细胞突变可以在Plk1,Tssk2和/或SMG1基因中。
另一方面,本发明涉及一种筛选用于治疗肿瘤的药物候选物的方法,其包括(a)将药物候选物施用于权利要求1的荷瘤非人动物,并(b)测量所述肿瘤对所述治疗的响应。
在一个实施方案中,步骤(b)包括评估所述药物候选物引起至少一种选自下组的响应的能力:减少肿瘤细胞数目,缩小肿瘤尺寸或肿瘤负荷,抑制肿瘤细胞浸润入周围器官,抑制肿瘤转移,和抑制肿瘤生长。
在另一个实施方案中,所述肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
在还有另一个实施方案中,所述肿瘤选自下组:乳腺癌,卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌,子宫内膜癌,白血病和中枢神经系统恶性肿瘤。
在又一个实施方案中,所述肿瘤为乳腺癌。
一不同方面,本发明涉及一种鉴定用于治疗药物抗性癌症的抗癌剂的方法,其包括(a)将药物候选物施用于权利要求1的荷瘤非人动物,(b)测量所述 肿瘤对所述治疗的响应,并(c)若所述肿瘤对所述治疗展现正面响应,则将所述药物候选物鉴定为用于治疗药物抗性癌症的抗癌剂。
在一个实施方案中,所述正面响应选自下组:减少肿瘤细胞数目,缩小肿瘤尺寸或肿瘤负荷,抑制肿瘤细胞浸润入周围器官,抑制肿瘤转移,和抑制肿瘤生长。
在另一个实施方案中,所述肿瘤选自下组:乳腺癌,卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌,子宫内膜癌,白血病和中枢神经系统恶性肿瘤。
在一个具体实施方案中,所述肿瘤为乳腺癌。
附图简述
图1。PIK3CAe20H1047R可条件性激活敲入等位基因的生成。a-d.显示(a)编码PIK3CA基因座的基因组基因座,(b)打靶构建物,(c)靶定等位基因,(d)ES中消除新霉素盒后的靶定基因座和(e)Cre介导的激活后的PIK3CAe20H1047R等位基因。f-g.通过使用5’探针(f)和3’探针(g)进行的Southern印迹来鉴定恰当靶定的敲入(ki)和野生型(wt)等位基因。h-i.Cre介导的激活后自PIK3CAe20H1047R/+乳腺(h)和肾(i)获得的cDNA的Sanger测序确认突变型等位基因在乳腺中的表达。
图2。PIK3CAe20H1047R小鼠发生乳腺肿瘤。a-b.在腹部乳腺(a)和胸部乳腺(b)中携带肿瘤的小鼠。白色箭头指向肿瘤的位置。c.描绘MMTV-Cre介导的潜伏PIK3CAe20mwt等位基因激活后两个独立PIK3CAe20H1047R系的无肿瘤存活的Kaplan-Meier图。图中只显示在终点时携带乳腺肿瘤的动物(~2500mm3;在研究中观察到86.4%的1系和84.2%的2系PIK3CAe20H1047R/+雌性小鼠发生了肿瘤)。两个对照组(MMTV-Cre小鼠和PIK3CAe20mwt)在研究期间没有肿瘤。d-g.PIK3CAe20H1047R乳腺肿瘤的组织学。H&E染色的肿瘤切片的分析显示存在多种组织学类型,包括纤维腺癌(d),腺鳞癌(e),腺癌(f)和纺锤细胞肿瘤(g)。h.代表各组织学类型的PIK3CAe20H1047R乳腺肿瘤的Western印迹显示与对照乳腺(1-2道)相比,所有肿瘤类型中升高的pAKT水平(3-10道)和pS6。肿瘤9,10衍生自原代纺锤肿瘤在SCID小鼠乳房脂肪垫中传代。
图3。PIK3CAe20H1047R乳腺肿瘤的免疫荧光染色。a-p.纤维腺癌(a-d),腺癌(e-h和i-l)和纺锤细胞肿瘤(m-p)用H&E(a,e,l和m),抗CK18和 抗CK5(b,f和j),抗ERα(c,g和k),抗Erα和抗PR(o),抗PR(d,h和l),和抗CK18和抗波形蛋白(n,p)抗体染色的连续切片。(p)中的切片是自第三次传代纺锤细胞肿瘤外植体获得的。
图4。PIK3CAe20H1047R驱动乳腺肿瘤的表达概况和基因组异常。a.使用所示基因集合的表达水平,通过组织学不同乳腺肿瘤类型的分级聚簇衍生的热图。不同组织学类型的乳腺肿瘤显示不同表达概况。样品描绘为纺锤细胞肿瘤(1-4;2-4是自1衍生的连续传代),对照乳腺(Mg)(5-10),纤维腺癌(11-15)和腺癌(16-20)。肿瘤样品17和18衍生自肿瘤16的连续传代。类似地,肿瘤样品18衍生自肿瘤11传代。对照乳腺样品6,9和10是来自分别携带肿瘤12,13和14的动物的匹配样品。b.全外显子组测序鉴定出纺锤细胞肿瘤中的自发性TP53突变。显示基因组区域,TP53外显子(突变以红色显示),来自感兴趣区域的读数(以实线描绘,突变位置以红色点显示)和TP53的结构域架构上的突变。PR,富含脯氨酸的结构域;Reg,羧基末端调节域;TA,反式激活域;Tet,四聚化结合域。c.CGH分析揭示纺锤细胞肿瘤中NF-1的丧失。
图5。PI3K抑制剂的体内抗肿瘤活性。a.作为异种移植物生长的PIK3CAe20H1047R乳腺肿瘤外植体响应GDC-0941治疗。图上显示每种治疗剂量(所有剂量n=9)相对于对照(n=9)的百分比肿瘤生长抑制。b.来自用GDC-0941治疗的动物的肿瘤显示PI3K途径抑制的证据。
图6。表达PIK3CAe20H1047R/+的乳腺显示过度侧分支和存在肿瘤小结。来自12周(a,b)和50周(c,d,e,和f)龄MMTV-Cre(a,c和e)或PIK3CAe20H1047R/+(b,d和f)小鼠的腹部乳腺的Carmine明矾染色的全封固(a-d)或H&E染色的切片(e,f)。
图7。经产和未产分组的无肿瘤存活。经产(465天)和未产(492天)中的中值无肿瘤存活的Kaplan-Meier分析具有统计学差异(时序检验p值=0.0002)。图中只显示在终点时携带乳腺肿瘤动物。
图8。来自PIK3CAe20mwt(a,c)或PIK3CAe20H1047R/+(b,d)的精囊(a,b)和唾液腺(c,d)的组织学。
图9。原代和传代肿瘤的组织学比较。a-f.(a)中的纤维腺癌在传代时产生(b)中所示纺锤细胞肿瘤。类似地,(c)中的纤维腺癌在传代时产生(d)中所示腺癌。然而,纺锤细胞肿瘤(e)在传代时维持其具有侵入性特征的纺锤细胞组织学(f)。
图10。原代肿瘤和传代肿瘤中按肿瘤类型分的预测体细胞突变的热图呈现。显示通过SIFT(Ng,P.C.& Henikoff,S.,Genome Res12,436-46(2002))预测的,突变对基因功能的影响,有害,耐受,和未记录(未称为影响)。1,2和3是三份不同纤维腺癌,4-6是腺癌。5和6是自两份独立肿瘤4外植体在小鼠中传代衍生的肿瘤。7-10是纺锤细胞肿瘤。肿瘤7外植体在小鼠中连续传代,衍生肿瘤8,9和10。
图11。以所示剂量用PI3K抑制剂治疗的荷瘤小鼠的进展前时间的Kaplan-Meier分析。
图12。打靶模板载体。该载体工程化改造为提供用于进行克隆的独特限制酶位点和生成打靶载体需要的其它元件。
图13。自PIK3CAe20mwt/+x PIK3CAe20mwt/+杂交获得的后代的基因型。
图14。用于基因组分析的样品。
表1。肿瘤中的预测体细胞突变。
发明详述
I.定义
除非另有定义,本文中使用的技术和科学术语具有与本发明所属领域普通技术人员常规理解相同的含义。Singleton et al.,Dictionary of Microbiology and Molecular Biology2nd ed.,J.Wiley&Sons(New York,N.Y.1994)。本领域技术人员会认识到可以使用与本文所述方法和材料相似或等同的许多方法和材料来实施本发明。确实,本发明绝非限于记载的方法和材料。为了本发明,下文定义了下述术语。
如本文中使用的,术语“等位基因”、“等位变体”、或“等位变异”可互换使用,指占据相同染色体基因座的基因的两种或更多种可选形式任一。等位变异经由突变天然发生,而且可导致群体内的表型多态性。基因突变可以是沉默的(编码的多肽没有变化),或是可以编码具有改变的氨基酸序列的多肽。术语“等位变体”在本文中还用于表示由基因的等位变体编码的蛋白质。典型地,基因的参照形式编码来自物种的单个参照成员或群体的多肽的野生型和/或优势型。典型地,等位变体(其包括种间变体)通常具有与来自同一物种的野生型和/或优势型的至少80%、90%或更大氨基酸同一性;同一性的程度取决于基因及比较是种间还是种内的。一般地,种内等位变体具 有与野生型和/或优势型的至少约80%、85%、90%或95%同一性或更大,包括与多肽的野生型和/或优势型的96%、97%、98%、99%或更大同一性。
当受试者具有一种基因的两个相同等位基因时,就说该受试者对于该基因或等位基因是纯合的。当受试者具有一种基因的两个不同等位基因时,就说该受试者对于该基因是杂合的。特定基因的等位基因可以彼此相差单个核苷酸或数个核苷酸,而且可以包括核苷酸替代、删除和插入。基因的等位基因也可以是基因含有突变的形式。
如本文中使用的,表述“条件性表达”意图指基因在条件达到时转录,而基因在条件未达到时不转录。条件性表达可以由细胞天然实现或实施(即没有人为干预),或者可以人为实现或实施(即有人为干预的参与,诸如例如但不限于使用化学试剂来调节的区域或启动子的使用,等等)。条件性表达可以例如通过由位点特异性重组酶触发的重组事件(其导致休眠基因的激活)(诸如由Cre介导的重组)来启动。
术语“核酸”指多核苷酸诸如脱氧核糖核酸(DNA)和适当时的核糖核酸(RNA)。作为等同物,该术语还包括自核苷酸类似物生成的DNA或RNA类似物及适用时的单链(有义链或反义链)和双链多核苷酸。“分离的”核酸分子指如下的核酸分子,其自/与在该核酸的天然来源中通常与之有关的至少一种污染性核酸分子鉴定和分开。分离的核酸分子在形式和背景方面不同于在自然界中找到它时。因此,分离的核酸分子有别于存在于天然细胞中时的核酸分子。然而,分离的核酸分子包括通常表达所编码的蛋白质的细胞中含有的核酸分子,其中例如该核酸分子处于与天然细胞的染色体位置不同的染色体位置。
如本文中使用的,术语“载体”指能够运输与其连接的另一核酸的核酸分子。术语“表达载体”包括能够合成由载体携带的相应重组基因编码的主题蛋白质的质粒、粘粒或噬菌体。优选的载体是能够自主复制和/或表达与它们连接的核酸的载体。在本说明书中,“质粒”和“载体”可互换使用,因为质粒是载体的最常用形式。
如本文中使用的,术语“转录调节元件”和“转录调节序列”可互换使用,指可操作连接的编码序列在特定宿主生物体中表达所必需的核酸,例如DNA序列。例如,适合于原核生物的控制序列包括启动子、任选的操纵基因序列、和核糖体结合位点。已知真核细胞利用启动子、增强子、剪接信号和 聚腺苷酸化信号。这些术语意图涵盖所有促进或调节转录的元件,包括启动子、RNA聚合酶和转录因子的基本相互作用所需要的核心元件、上游元件、增强子、和应答元件(Lewin,"Genes V"(Oxford University Press,Oxford)第847-873页)。本文中提到一种基因或一类基因的转录调节元件包括该基因或该组基因的天然存在转录调节元件和经修饰形式的转录调节元件的所有或完整区域二者。此类经修饰形式包括元件的重排、一些元件或外来序列的删除、及异源元件的插入。转录调节元件的模块化性质和一些调节元件(诸如增强子)的功能的位置依赖性的缺失使得此类修饰成为可能。众多技术可用于解剖基因的调节元件以确定它们的位置和功能。此类信息可用于指导元件的修饰,若想要的话。然而,优选的是,使用基因的转录调节元件的完整区域。
若一段核酸与另一段核酸序列处于功能性相互关系中,则它是“可操作连接的”。例如,若前序列(presequence)或分泌前导(secretory leader)的DNA表达成参与多肽分泌的前蛋白质(preprotein),则它与该多肽的DNA可操作连接;若启动子或增强子影响编码序列的转录,则它与该序列可操作连接;或者,若核糖体结合位点的位置促进翻译,则它与编码序列可操作连接。一般而言,“可操作连接的”意味着相连的DNA序列是相邻的,而且在分泌前导的情况中意味着相邻且处于阅读状态。然而,增强子不必相邻。连接可以通过在方便的限制性位点处的连接来实现。若没有此类位点,则依照常规实践使用合成的寡核苷酸衔接头或接头。
术语“转染”指通过核酸介导的基因转移将核酸(例如表达载体)导入受体细胞。如本文中使用的,“转化”指如下的过程,其中细胞的基因型因细胞摄取外源DNA或RNA而改变,且经过转化的细胞表达期望异源蛋白。
如本文中使用的,术语“转基因”指如下的核酸序列,即它对于它导入的转基因动物或细胞是部分或完全异源的(即外来的),或对于它导入的转基因动物或细胞的内源基因是同源的,以使得改变它插入的细胞的基因组(例如将它插入与天然基因的位置不同的位置或它的插入导致敲除)的方式插入或设计插入动物的基因组。转基因可以可操作连接至一种或多种转录调节序列和选定核酸的最佳表达可能必需的任何其它核酸(诸如内含子)。
因而,术语“转基因构建物”指包括转基因和(任选的)诸如转录调节序列、聚腺苷酸化位点、复制起点、标志基因、等其它核酸序列的核酸,其 可用于将转基因插入宿主生物体的基因组的一般操作。
术语“转基因”在本文中作为形容词用于描述例如动物或构建物包含转基因的特性。例如,如本文中使用的,“转基因生物体”指任何动物,优选非人哺乳动物,更优选啮齿类动物,其中动物的一个或多个细胞含有通过人为干预引入的异源核酸,诸如例如通过本领域公知的转基因技术。通过精细遗传操作,诸如通过显微注射或通过重组病毒感染,直接地或间接地通过导入细胞前体将核酸导入细胞。术语“遗传操作”不包括经典的杂交育种或体外受精,而是指向引入重组DNA分子。此分子可以在染色体内整合,或者它可以是染色体外复制DNA。
“敲除”基因表示导致靶基因的功能降低的基因序列改变,优选使得靶基因表达检测不到或不显著。转基因敲除动物可包含靶基因的杂合敲除或靶基因的纯合敲除。如本文中使用的,“敲除”还包括条件性敲除,其中在例如将动物暴露于促进靶基因改变的底物、引入促进靶基因位点处的重组的酶(例如Cre-lox系统中的Cre)、或用于出生后指导靶基因改变的其它方法时,可发生靶基因的改变。
“敲入”指将转基因靶向插入宿主细胞基因组,导致转基因的表达和/或内源靶基因改变的表达(例如升高的(包括异位的)或降低的表达),例如通过引入额外拷贝的靶基因或通过操作性插入提供内源拷贝的靶基因增强的表达的调节序列。“敲入”转基因可包含转基因的杂合敲入或转基因的纯化敲入。“敲入”还涵盖条件性敲入,其中例如将动物暴露于促进此类表达的物质、通过引入促进靶向插入位点处的重组的酶(例如Cre-lox系统中的Cre)、或通过用于改变靶向插入位点的一些其它方法,可发生转基因的表达和/或内源靶基因改变的表达。
“纯化”状态表示相同等位基因驻留于同源染色体上的相应基因座时存在的遗传条件。相反,“杂合”状态表示不同等位基因驻留于同源染色体上的相应基因座时存在的遗传状态。
“位点特异性重组酶”指在一些病毒和细菌中存在且表征为具有内切核酸酶和连接酶二者特性的酶。位点特异性重组酶催化至少下述四种事件:(a)删除侧翼为相同取向(例如头对尾或尾对头)的“相容位点特异性重组酶靶向位点”(SSRTS)的DNA片段;(b)颠倒侧翼为相反取向(例如头对头或尾对尾)的相容SSRTS的DNA片段;(c)将含有SSRTS的环状DNA片段整合入相 容SSRTS;和(d)位于不同染色体的相容SSRTS之间的染色体易位。为了实施这些反应,位点特异性重组酶通常具有至少下述四种活性:(1)识别一种或两种特定DNA序列;(2)切割所述DNA序列;(3)涉及链交换的DNA拓扑异构酶活性;和(4)重新密封经过切割的DNA链的DNA连接酶活性(Sauer,B.,Cur.Opin.Biotech.5:521-527,1994)。
术语“重组酶”或“位点特异性重组酶”指进行位点特异性重组(SSR)以改变DNA结构的酶。这种定义包括转座酶、拉姆达(λ)整合/切除酶、和位点特异性重组酶。重组酶的公知例子包括但不限于Cre-lox、FLP/FRT、R/RS、Gin/gix、pSR1系统、cer系统、和fim系统(例如N.L.Craig,Annu.Rev.Genet.22:17,1988;Odell et al.,Homologous Recomb.Gene Silencing Plants,1994,pp.219-270,Paszkowski,Jerzy,ed.Kluwer:Dordrecht,Germany)。另外,已经在微生物中鉴定了SSR系统,诸如噬菌体、细菌(例如大肠杆菌)、酵母等等。这包括用于整合和切除的大肠杆菌λatt P系统(Zubko et al.,Nature Biotechnology18:442,2000)和链霉素噬菌体C31整合酶(Groth et al.,Proc.Natl.Acad.Sci.USA97:5995,2000)。在将来自这些微生物的SSR系统引入与衍生这种系统的生物体不同的生物体(包括植物)时,它的表现方式与在初始生物体中相同。
“重组酶位点”或“位点特异性重组序列”表示会受到重组酶识别,从而推动重组事件的DNA序列。会领会,这可以是野生型或突变型重组酶位点,只要功能性得到维持且重组酶仍可识别该位点,结合DNA序列,并催化两个相邻重组酶位点之间的重组。
术语“lox侧翼”指遗传元件或其部分侧翼为串联位点特异性序列。位点特异性序列可以彼此以相同方向(即同向重复)(使得DNA元件在SSR时切除)或以相反方向(使得DNA元件在SSR时颠倒)取向。lox侧翼元件可以是单一启动子、转录“终止”阻断元件、可操作连接靶序列的启动子、或这些和其它遗传元件的组合。
“位点特异性重组底物”或“SSR底物”指如下的任何DNA,它是SSR的底物,SSR源自位点特异性重组酶对重组酶位点的作用。该术语包括lox侧翼DNA元件,即那些侧翼为重组酶位点的DNA元件。
术语“建立者系”和“建立者动物”指如下的那些动物,它们是添加有转基因的胚胎的成熟产物,即那些自插入有DNA并植入一个或多个代孕宿主 的胚胎生长起来的动物。
术语“后代”和“转基因动物的后代”指最初转化的哺乳动物之后的每一代的任何和所有后裔。
术语“哺乳动物”指哺乳纲的所有成员,包括人、高等灵长类动物、家畜和牲畜诸如家兔、猪、绵羊、山羊、牛、及动物园、运动、或宠物动物、及啮齿类动物诸如小鼠和大鼠。
术语“非人哺乳动物”指哺乳纲除人以外的所有成员。
在用于本文时,表述“细胞”、“细胞系”和“细胞培养物”可互换使用,而且所有这类名称都包括后代。如此,词语“转化子/转化体”和“转化细胞”包括原代受试细胞及由其衍生的培养物,不管转移的次数。还应理解,由于有意的或无意的突变,所有后代可能在DNA内容上不是精确相同的。在最初转化细胞中筛选的具有相同功能或生物学活性的突变后代包括在内。若想做出不同的命名,上下文会有清楚的表述。
如本文中使用的,“肿瘤”指所有赘生性(neoplastic)细胞生长和增殖,无论是恶性的还是良性的,及所有癌前(pre-cancerous)和癌性细胞和组织。
术语“癌症”和“癌性”指或描述哺乳动物中特征通常为细胞生长不受调节的生理状况。癌症的例子包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤、及白血病或淋巴样恶性肿瘤。此类癌症的更具体例子包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌包括小细胞肺癌、非小细胞肺癌、肺的腺癌和肺的鳞状癌、腹膜癌、肝细胞癌、胃癌包括胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝肉瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、以及头和颈癌。
如本文中使用的,术语“细胞毒剂”指抑制或阻止细胞功能和/或引起细胞破坏的物质。该术语意图包括放射性同位素(例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32和Lu的放射性同位素)、化疗剂、和毒素诸如小分子毒素或者细菌、真菌、植物或动物起源的酶活毒素,包括其片段和/或变体。
“化疗剂”指可用于治疗癌症的化学化合物。化疗剂的例子包括烷化剂类,诸如噻替哌(thiotepa)和环磷酰胺烷基磺酸酯类,诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡 (piposulfan);氮丙啶类,诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(曲大麻酚(dronabinol),β-拉帕醌(lapachone);拉帕醇(lapachol);秋水仙素类(colchicine);白桦脂酸(betulinic acid);喜树碱(camptothecin)(包括合成类似物拓扑替康(topotecan) CPT-11(伊立替康(irinotecan),乙酰喜树碱、东莨菪素(scopolectin)和9-氨基喜树碱);苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);隐藻素类(cryptophycin)(特别是隐藻素1和隐藻素8);多拉司他丁(dolastatin);duocarmycin(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类,诸如氯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌氮芥(estramustine)、异磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、松龙苯芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲类,诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,诸如烯二炔类(enediyne)抗生素(如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(参见例如Agnew,Chem.Intl.Ed.Engl.33:183-186(1994));蒽环类(dynemicin)抗生素,包括dynemicin A;埃斯波霉素(esperamicin);以及新抑癌菌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、氨茴霉素(authramycin)、氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素 (carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星、盐酸多柔比星脂质体注射剂脂质体多柔比星TLC D-99PEG化脂质体多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培来霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨喋呤、吉西他滨替加氟(tegafur) 卡培他滨epothilone和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨喋呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、多西氟尿啶(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);抗肾上腺类,诸如氨鲁米特(aminoglutethimide)、曼托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;醋葡内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基酮戊酸(aminolevulinic acid);恩尿嘧啶(eniluracil);氨苯吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;地美可辛(demecolcine);地吖醌(diaziquone);依洛尼塞(elfornithine);醋酸羟吡咔唑(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟脲;香菇多糖(lentinan);氯尼达明(lonidamine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和美登醇(maytansinol);安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼;丙卡巴肼(procarbazine); 多糖复合物(JHS Natural Products,Eugene,Oreg.);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2''-三氯三乙胺;单端孢菌素类(trichothecene)(尤其是T-2毒素、verracurin A、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦(urethan);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);噻替哌;类紫杉醇(taxoid),例如帕利他赛紫杉醇的清蛋白改造纳米颗粒剂型和多西他赛苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤;巯基嘌呤;甲氨喋呤;铂剂,诸如顺铂、奥沙利铂(oxaliplatin)和卡铂;阻止微管蛋白聚合形成微管的长春花生物碱类(vincas),包括长春碱长春新碱(vincristine) 长春地辛和长春瑞宾依托泊苷(etoposide)(VP-16);异磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);亚叶酸(leucovovin);诺安托(novantrone);依达曲沙(edatrexate);柔红霉素(daunomycin);氨基蝶呤;伊拜膦酸盐(ibandronate);拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类维A酸,诸如视黄酸,包括贝沙罗汀二碳磷酸盐类(bisphosphonate),诸如氯膦酸盐(clodronate)(例如 或 NE-58095、唑来膦酸(zoledronic acid)/唑来膦酸盐/酯阿仑膦酸盐/酯替鲁膦酸盐/酯 或利塞膦酸盐/酯曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是那些抑制涉及粘着性细胞增殖的信号途经中的基因表达的反义寡核苷酸,诸如例如PKC-α、Ralf、H-Ras和表皮生长因子受体(EGF-R);疫苗,诸如疫苗和基因疗法疫苗,例如疫苗、 疫苗和疫苗;拓扑异构酶1抑制剂(如 BAY439006(sorafenib;Bayer);SU-11248(Pfizer);哌立福辛(perifosine),COX-2抑制剂(如塞来考昔(celecoxib)或艾托考昔(etoricoxib)),蛋白体抑制剂(如PS341);bortezomib CCI-779;tipifarnib(R11577);orafenib,ABT510;Bcl-2抑制剂,诸如pixantrone;EGFR抑制剂(见下文定义);酪氨酸激酶抑制剂(见下文定义);及上述任何物质的药学可接受的盐、酸或衍生物;以及上述两种或多种的组合,诸如CHOP(环磷酰胺、多柔比星、长春新碱和泼尼松龙联合疗法的缩写)和FOLFOX(奥沙利铂联合5-FU和亚叶酸(leucovovin)的治疗方案的缩写)。
术语“前体药物”在用于本申请时指与母药(parent drug)相比对肿瘤细胞的细胞毒性较小并能够酶促活化或转变为更具活性母药形式的药用活性物质的前体和衍生物形式。参见例如Wilman,“Prodrugs in Cancer Chemotherapy”,Biochemical Society Transactions,14,pp.375-382,615th Meeting Belfast(1986)和Stella et al.,“Prodrugs:A Chemical Approach to Targeted Drug Delivery”,Directed Drug Delivery,Borchardt et al.,(ed.),pp.247-267,Humana Press(1985)。本发明的前体药物包括但不限于含磷酸盐/酯前体药物、含硫代磷酸盐/酯前体药物、含硫酸盐/酯前体药物、含肽前体药物、D-氨基酸修饰前体药物、糖基化前体药物、含β-内酰胺前体药物、含任选取代苯氧基乙酰胺的前体药物或含任选取代苯乙酰胺的前体药物、可转化为更具活性而无细胞毒性的药物的5-氟胞嘧啶和其它5-氟尿苷前体药物。可衍生为本发明使用的前体药物形式的细胞毒性药物的例子包括但不限于上文描述的那些化疗剂。
“脂质体”指由各种类型的脂质、磷脂和/或表面活性剂构成的,可用于对哺乳动物投递药物(诸如本文中所披露的抗ErbB2抗体和任选的化疗剂)的小囊泡。脂质体的成分通常排列成双层形式,与生物膜的脂质排列相似。
“小分子”在本文中定义为具有约500道尔顿以下的分子量。
术语“抗体”在本文中以最广义使用,明确覆盖完整的单克隆抗体、多克隆抗体、由至少两种完整抗体形成的多特异性抗体(例如双特异性抗体)、及抗体片段,只要它们展现出期望的抗原结合活性。
术语“单克隆抗体”在用于本文时指从一群基本上同质的抗体获得的抗体,即构成群体的各个抗体相同,除了可能以极小量存在的可能的天然存在突变形式外。单克隆抗体是高度特异性的,针对单一抗原性位点。此外,与包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物不同,每种单克隆抗体针对抗原上的单一决定簇。在它们的特异性以外,单克隆抗体的优 势在于它们可以在不受其它抗体污染的情况下合成。修饰语“单克隆”指示抗体从基本上同质的抗体群获得的特征,不应解释为要求通过任何特定方法来生成抗体。例如,有待依照本发明使用的单克隆抗体可以通过首次由Kohler et al.(1975)Nature256:495记载的杂交瘤方法来制备,或者可以通过重组DNA方法来制备(参见例如美国专利No.4,816,567)。“单克隆抗体”也可以使用例如Clackson et al.(1991)Nature352:624-628及Marks et al.(1991)J.Mol.Biol.222:581-597中记载的技术从噬菌体抗体库分离。
单克隆抗体在本文中明确包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(参见美国专利No.4,816,567;Morrison et al.,Proc.Natl.Acad.Sci.USA81:6851-6855(1984))。本文中感兴趣的嵌合抗体包括包含衍生自非人灵长类动物(例如旧大陆猴类(Old World Monkey)、猿等)的可变域抗原结合序列和人恒定区序列的“灵长类化”抗体。
“抗体片段”包含完整抗体的一部分,优选包含抗体的抗原结合区或可变区。抗体片段的例子包括Fab、Fab'、F(ab')2和Fv片段;双抗体;线性抗体;单链抗体分子;及由抗体片段形成的多特异性抗体。
“完整”抗体指包含抗原结合可变区以及轻链恒定区(CL)和重链恒定区CH1、CH2和CH3的抗体。恒定区可以是天然序列恒定区(例如人天然序列恒定区)或其氨基酸序列变体。优选的是,完整抗体具有一项或多项效应物功能。
非人(例如啮齿类动物)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。在极大程度上,人源化抗体指人免疫球蛋白(受体抗体)中的高变区残基用具有期望特异性、亲和力和能力的非人物种(供体抗体)诸如小鼠、大鼠、兔或非人灵长类动物的高变区残基替换的免疫球蛋白。在有些情况中,将人免疫球蛋白的框架区(FR)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体中或在供体抗体中没有找到的残基。进行这些修饰是为了进一步改进抗体的性能。一般而言,人源化抗体将包含至少一个、通常两个基本上整个如下的可变域,其中所有或基本上所有高变环对应于非人免疫球蛋白的高变环,且所有或基本上所有FR 是人免疫球蛋白序列的FR。人源化抗体任选还将包含至少部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。更多细节参见Jones et al.,Nature321:522-525(1986);Riechmann et al.,Nature332:323-329(1988);和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
II.详细描述
癌症的条件性PIK3CA
H1047R
非人动物模型的生成
如上文讨论的,IA类PI3K催化亚基p110α,p110β和p110ó作为与p85α,p55α,p50α,p85β或p55γ调节亚基复合的专性异二聚体存在。在正常细胞中,PI3K维持于基础无活性状态且在生长因子刺激和细胞表面受体参与后变成有活性。活化的PI3K磷酸化并转化磷脂酰肌醇4,5二磷酸酯(PIP2),产生磷脂酰肌醇3,4,5三磷酸酯(PIP3)。升高的细胞PIP3水平促进PI3K效应器活化,其继而调节多种细胞过程,包括细胞生长,增殖和存活。
超过25%的人乳腺癌中发生编码磷脂酰肌醇3-激酶(PI3K)催化亚基p110α的PIK3CA中的致癌性突变。还已经在其它类型的人癌症中报告了PIK3CA基因中的频繁突变,诸如卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌和子宫内膜癌,急性白血病和中枢神经系统恶性肿瘤。
本发明至少部分基于乳腺癌的敲入小鼠模型的开发,其中内源PIK3CA等位基因经过修饰而容许频繁发现的PIK3CA H1047R(PIK3CAe20H1047R)突变型等位基因的组织特异性条件性表达。特别地,通过放置一休眠拷贝包括H1047R的致癌性突变型PIK3CA外显子,与野生型编码外显子相邻,修饰内源PIK3CA等位基因。在休眠突变型等位基因激活之前,工程化小鼠表达经修饰野生型PIK3CA(PIK3CAe20mwt)。然而,在Cre介导的重组时,突变型PIK3CA H1047R等位基因(PIK3CAe20H1047R)被激活,导致其表达。本文中呈现的结果显示小鼠乳腺上皮中PIK3CA H1047R等位基因的条件性激活导致突变型PIK3CA H1047R表达和肿瘤发生。而且,在实施来自这种模型的纺锤细胞肿瘤的全外显子组分析时,自发性功能丧失性TP53突变的出现被鉴定为涉及肿瘤形成的潜在合作事件。
发现潜伏PIK3CA H1047R等位基因的激活导致具有多种组织学类型的乳腺肿瘤。与PIK3CAe20H1047R的表达一致,所有肿瘤显示PI3K途径的激活。而且,PIK3CA H1047R驱动的乳腺肿瘤的全外显子组分析鉴定出多种突变,包括已经充分表征的在纺锤细胞型肿瘤发生期间自发出现的TP53热点突变。 在演示该模型在研究肿瘤发生期间次要突变出现中的效用之外,还使用这种小鼠模型测试处于临床开发的PI3K-抑制剂GDC-0941的功效,而且显示肿瘤响应PI3K抑制。因而,本文中开发的转基因非人动物模型是研究肿瘤启动,进展和治疗的有价值工具,而且自身还适于鉴定在肿瘤发生期间与突变型PIK3CA合作的损伤。特别地,本发明的非人转基因动物模型可用于筛选抗癌剂,而单独或任意组合的PIK3CAe20H1047R和次要突变可用于癌症的诊断,分类,预后,和治疗,包括但不限于乳腺癌。
在生成本发明的转基因小鼠时,使用Cre-lox重组系统。Cre蛋白是一种位点特异性DNA重组酶,它能催化DNA分子中特定位点之间的DNA重组。这些位点(称作loxP序列)含有Cre的特异性结合位点,它们围绕定向核心序列,在那里可发生重组。当在其基因组中具有loxP位点的细胞表达Cre时,loxP位点之间可发生重组事件。双链DNA在两个loxP位点处都受到Cre蛋白切割。然后用DNA连接酶重新接合链。重组的结果取决于loxP位点的取向。对于在相同染色体臂上的两个lox位点,颠倒的loxP位点会引起插入,而同向重复的loxP位点会引起删除事件。
虽然Cre-lox重组系统最初是为了用于在哺乳动物细胞系和转基因小鼠中激活基因表达而开发的,但是后来显示Cre-lox重组可用于在转基因动物的多种选定细胞类型中高效删除侧翼为loxP的染色体DNA序列,而且Cre-lox重组可用于体内条件性基因打靶。另外,可使用其它定点重组系统(包括上文所列那些)来生成与本文中具体例示的小鼠模型相似的非人转基因动物模型。
由于PIK3CA突变在乳腺癌中的重要性,测试了PIK3CA H1047R等位基因在乳腺肿瘤发生中的作用,这通过将PIK3CAe20mwt小鼠与MMTV-Cre转基因小鼠(其中在乳腺允许性MMTV LTR启动子控制下表达Cre重组酶)交配来进行。对于其它类型的肿瘤,可使用其它组织允许性或组织特异性启动子。组织特异性启动子(包括导致特定组织类型或器官,诸如肝,胰,肾,肝,肺,睾丸表达的调节元件)是本领域已知的且可得的,例如得自TiProD人启动子序列数据库,它们的一些功能特征是已知的。该数据库容许用户查询个别启动子和它们介导的表达样式,及依照它们的组织特异性活性找出启动子集合。可生成PIK3CA突变在其中发挥作用的其它癌症类型的非人转基因动物模型,例如通过使用本领域已知的适宜组织特异性启动子之一。
可以通过任何合适方法对本发明的转基因非人动物(包括它们的后代)筛选转基因的存在和/或表达。筛选常常通过使用与至少部分转基因互补的探针进行的自尾组织制备的DNA的Southern印迹或PCR来实现。可开发使用针对由转基因编码的蛋白质的抗体进行的Western印迹分析或免疫组织化学,作为用于筛选转基因产物的存在的替代或补充方法。或者,使用Northern分析或RT-PCR对认为以最高水平表达转基因的组织或细胞测试转基因的RNA表达。
用于评估转基因存在情况的替代或补充方法包括但不限于合适的生物化学测定法,诸如酶和/或免疫学测定法,针对特定标志物或酶活性的组织学染色剂,流式细胞术分析,等等。血液分析也可用于检测血液中转基因产物的存在情况,以及在各种类型的血液细胞和其它血液组分的水平上评估转基因的效果。
候选抗癌剂的筛选
本发明的非人转基因动物模型可用于对候选药剂筛选抗癌活性。术语“抗癌活性”以最广义使用,包括直接或间接介导预防,延迟,减缓或抑制肿瘤发生和/或生长方面的任何效果的活性,这可以给宿主提供有益效果。“抗癌活性”因此涵盖但不限于直接或间接减少癌细胞数目,缩小肿瘤尺寸或肿瘤负荷,抑制(即一定程度地减缓和优选终止)癌细胞浸润入周围器官,抑制(即一定程度地减缓和优选终止)肿瘤转移,一定程度地抑制肿瘤生长,和/或一定程度的减轻一种或多种与癌症有关的症状的能力。
对可临床用于治疗癌症的具有抗癌活性的药剂特别感兴趣。在本公开中特别感兴趣的是鉴定可在治疗特征为PIK3CA中的致癌性突变(特别是突变型PIK3CA H1047R等位基因或次要突变激活)的癌症中提供临床好处的具有抗癌活性的药剂。
一般地,通过在非人转基因动物模型中评估对癌症表型的影响的存在或缺乏来评估抗癌活性,该对癌症表型的影响指示候选药剂的抗癌活性。如此,例如,施用候选药剂后动物中的肿瘤负荷降低指示该药剂具有抗癌活性。
可使用本发明的非人动物模型筛选抗癌活性的候选抗癌剂包括但不限于合成的,天然存在的,或重组生成的分子,包括小分子,肽,抗体和其它多肽。
可以自极其多种来源获得候选药剂,包括合成或天然化合物的文库。例 如,众多手段可用于随机和定向合成极其多种有机化合物和生物分子,包括表达随机化寡核苷酸和寡肽。或者,细菌,真菌,植物和动物提取物形式的天然化合物文库是可得的或容易生成的。或者,经由常规化学,物理和生物化学手段容易修饰天然的或合成生成的文库和化合物,而且可用于生成组合文库。可以对已知药理学药剂进行定向或随机化学修饰,诸如酰化,烷化,酯化,酰胺化,等以生成结构类似物。
可以以对于投递药剂而言期望和/或适宜的任何方式施用候选药剂以检查抗癌活性。例如,可以通过注射(例如通过静脉内,肌肉内,皮下,等等注射),输注,口服,或通过任何其它期望手段来施用候选药剂。
筛选方法可涉及施用不同量的候选药剂(从没有药剂到接近可成功投递给动物的量上限的量的药剂,例如在毒性极限内),而且可以包括以不同配方和路径投递药剂。可以施用单一药剂,或者可以在两种或更多种药剂的组合中组合药剂,尤其是药剂组合的施用可导致协同效应的情况。
可以通过将候选药剂施用于转基因动物,并评估对癌症表型的调控来评估候选药剂治疗已有癌症的能力。可以例如通过评估对例如肿瘤负荷,肿瘤数目,肿瘤尺寸,肿瘤细胞的代谢活性,无进展存活(PFS),总体存活(OFS),等等的影响的存在或缺乏来评估对癌症表型的调控。
可以通过施用候选药剂,之后诱导导致肿瘤发生的突变来评估候选药剂推动癌症预防的能力。癌症预防指相对于在没有干预(例如不施用具有抗癌活性的药剂)的情况下预期的癌症发生率和/或严重性降低动物中的肿瘤发生率和/或严重性。
下面的非限制性实施例例示本发明的进一步详情。
实施例
可条件性激活的PIK3CAH1047R小鼠模型
材料和方法
可条件性激活的PIK3CA H1047R小鼠的生成
我们使用一种打靶载体模板(图1)来装配最终的打靶载体。使用来自C57B/6N ES细胞的小鼠基因组DNA作为模板,PCR扩增涵盖PIK3CA外显子18-19的2.045kb片段(左臂),含有PIK3CA野生型外显子20的588bp区域(中臂),和也含有外显子20和额外的3’内含子序列的3.137kb基因组DNA(左臂), 并用于构建载体。在克隆入模板打靶载体之前,使用标准诱变技术突变由左臂中外显子20编码的密码子1047以编码组氨酸(R1047H)。在将中臂克隆入打靶模板载体时,通过添加载体中存在的高polyA信号来修饰野生型外显子20区域。新霉素表达盒,4x转录终止盒(Jackson,E.L.et al.,Genes Dev15,3243-8(2001))也由载体提供。在最终的构造中,新霉素盒侧翼为‘frt’位点以推动其在ES细胞修饰后切除。还有,经修饰野生型外显子侧翼为‘loxP’位点以推动其切除,这能激活突变型外显子20(图1)。通过Sanger测序来检验打靶载体的准确性。将打靶构建物电穿孔入C57B/6N ES细胞,并选择新霉素抗性。通过5’和3’Southern印迹鉴定出恰当靶定的ES克隆。当AflII消化和Southern印迹后测试恰当靶定的基因组DNA时,5’探针识别6.6kb野生型片段和9.1kb片段。类似地,3’探针识别SacI消化后适当修饰的基因组区域的6.9kb野生型片段和4.8kb片段(图1c)。切除neo盒及使用PCR和测序确认编码PIK3CA的经修饰基因组区域的架构后,将ES克隆注射入胚泡以生成嵌合小鼠。与野生型小鼠中的201bp片段不同,利用使用引物20F(AGCCAGCAGACAATAATTCTTAGCACA)(SEQ ID NO:1)和20R(CAGTGCTTGAACATTGGAGGTCAGT)(SEQ ID NO:2)生成的290bpPCR产物来跟踪种系传递还有测定携带经修饰PIK3CA等位基因的小鼠的基因型。为了激活乳腺中的潜伏PIK3CA H1047R突变型等位基因,我们将这种小鼠与MMTV-Cre(Jackson labs#003551)系交配。对于我们的终点研究,跟踪具有可触知肿瘤的小鼠,直至肿瘤达到~2500mm3,然后处以安乐死。还有,对展现任何身体条件得分<2(Ullman-Cullere,M.H.&Foltz,C.J.B LabAnim Sci49,319-23(1999)),隆起姿态和体重损失>20%的小鼠也处以安乐死。依照科研动物护理和使用委员会(IACUC)指南在我们的动物房中维持所有小鼠。
DNA/RNA制备
使用Qiagen AllPrep DNA/RNA试剂盒(Qiagen,CA)制备来自肿瘤/组织的DNA。使用RNeasy迷你试剂盒(Qiagen,CA)制备RNA样品。
表达分析
分别使用ND-1000分光光度计(Thermo Scientific,DE)和Bioanalyzer2100(Agilent Technologies,CA)测定总RNA样品的数量和质量。按照制造商(Agilent Technologies,CA)的用法说明书制备Cy染料标记的cRNA和阵 列杂交。简言之,将总RNA样品转变成双链cDNA,然后使用Agilent的快速扩增标记试剂盒转变成Cy染料标记的cRNA。使用RNeasy迷你试剂盒(Qiagen,CA)纯化经过标记的cRNA。使用ND-1000分光光度计(Thermo Scientific,Wilmington,DE)测定cRNA产率和Cy染料掺入。将750ng经过标记的cRNA片段化,并与Agilent的小鼠全基因组4x44K阵列杂交。用Cy5染料标记所有样品,并与Cy3染料标记的通用小鼠参照(Stratagene,CA)杂交。将样品在Pro Hybridization station HS4800(Tecan US,NC)上以恒定摇动于65℃杂交17小时。杂交后,清洗阵列,干燥,并在Agilent扫描仪上扫描。使用Agilent的特征提取软件10.7来分析获得的阵列图像。
自公用参照设计实验中使用的两色Agilent微阵列获得基因表达数据。在Cy3通道中测量公用参照样品,在Cy5通道中测量感兴趣样品。使用limma R包(Smyth,G.K.,Stat Appl Genet Mol Biol3,Article3(2004))中执行的方法加工数据。首先,对数据修正背景,之后应用阵列内loess拟合和阵列间分位数标准化(Smyth,G.K.&Speed,T.,Methods31,265-73(2003))。使用limma的线性模型拟合获得差异表达基因标签,认为FDR调整p值为0.05或更低和log2变化为至少2的探针是差异表达的。使用欧几里得距离度量和完全连锁聚簇对均值集中基因表达概况计算样品和EMT相关基因的分级聚簇。
比较基因组杂交(CGH)测定法
依照制造商的方案(Agilent Technologies,CA)在Agilent CGH阵列上对来自PIK3CAe20H1047R小鼠的乳腺肿瘤样品测定概况。简言之,用Alu I和Rsa I(Promega,WI)消化肿瘤和参照样品(C57BL/6J小鼠,The JacksonLaboratory,ME)二者的500ng DNA,随后用QIAprep Spin Miniprep试剂盒(QIAGEN GmbH,Germany)纯化。使用升级版基因组DNA标记试剂盒(Agilent Technologies,CA)用Cy5-dUTP(测试样品)或Cy3-dUTP(参照样品)标记经过消化的样品。将测试样品与参照合并,随后使用MicroConYM-30(Millipore,Billerica,MA)纯化。将经过标记的探针与Cot-1DNA(Invitrogen,CA),10x封闭剂和2x Hi-RPM杂交缓冲液(Agilent Technologies,CA)混合,并与Agilent的244K小鼠基因组CGH微阵列杂交。将样品在ProHybridization station HS4800(Tecan US,NC)上以恒定摇动于67℃杂交24小时。清洗阵列,干燥,并依照制造商的方案(Agilent Technologies,CA)在Agilent扫描仪上扫描。自Agilent特征提取软件10.7版获得减去背景的信号 强度的个别log2比。将log2比集中至中值零,并使用GLAD(Hupe,P.,et al.,Bioinformatics20,3413-22(2004))对每种探针的所得log2比值分段。对给定GLAD衍生区段的基因组边界内的所有基因给予该区段内的探针的均值拷贝数值。拷贝数值>=0.4log2比单位代表增益,值<=-0.4log2比单位代表损失。
外显子组捕捉和测序
依照制造商的方案(Agilent Technologies,CA)使用3μg基因组DNA和SureSelectXT小鼠所有外显子试剂盒实施靶定序列捕捉。小鼠所有外显子试剂盒设计用于捕捉49.6Mb靶定区,而且覆盖24,306种基因内的221,784个外显子。使用四轮PCR扩增捕捉前文库,但在捕捉后扩增中使用12轮PCR。在Bioanalyzer2100上使用DNA高灵敏度芯片(Agilent Technologies,CA)测定捕捉后扩增文库的片段大小分布。通过卡帕文库定量试剂盒(Kapa Biosystems,MA)测量文库的浓度。按照制造商的用法说明书(Illumina,CA)在HiSeq2000上对每个文库测序以生成2x75bp读出。使用缺省参数设置的BWA软件(Li,H.& Durbin,R.,Bioinformatics25,1754-60(2009))将测序读出定位至UCSC小鼠基因组(NCBI37/mm9)。如先前描述的那样(DePristo,M.A.et al.,Nature Genetics43,491-498(2011))实施局部再比对,双份标记和原始变体呼叫。使用dbSNP Build131(Sherry,S.T.et al.,Nucleic Acids Res29,308-11(2001))中记载的SNP来清除已知的种系变异。另外,作为种系变异清除肿瘤和正常样品中都存在的变体。预测肿瘤样品中存在但匹配正常中缺失的剩余变异是体细胞的。另外过滤预测体细胞变异从而只包括具有肿瘤和匹配正常二者中最小10x覆盖以及匹配正常中观察变异等位基因频率<1%的位置。使用SIFT(Ng,P.C.& Henikoff,S.,Genome Res12,436-46(2002))和PolyPhen(Ramensky,V.,Bork,P.&Sunyaev,S.H.,Nucleic Acids Res30,3894-900(2002))预测蛋白质体细胞突变对基因功能的影响(表1)。
组织学,免疫组织化学和全封固分析
使用5μm,福尔马林固定,石蜡包埋标本进行例行苏木精和曙红(H&E)染色和组织学评估。
对于全封固分析,解剖乳腺,铺开,并用Carnoy氏固定剂固定2-4小时。将组织水合并在Carmine明矾中染色过夜。
使用10μm切片Tissue-Tek OCT(Sakura Finetek,CA)包埋冷冻样品实 施免疫荧光染色。将切片样品在4%多聚甲醛中固定10分钟,然后用含有1%BSA的PBT(含0.1%Triton的PBS)封闭30分钟。然后在增湿室中将经过封闭的切片用适宜的一抗(在含0.1%BSA的PBT中稀释)于4℃染色过夜。将载玻片在PBT中清洗3次,然后在增湿室中与适宜的二抗一起于室温温育60分钟。通过PBT清洗除去未结合的二抗。使用Prolong Gold抗褪色试剂(anti-fade reagent)(Invitrogen,CA)封固载玻片。研究中使用的一抗是细胞角蛋白5(Abcam,ab53121),细胞角蛋白18(Abcam,ab668),ERα(Thermo scientific,Ab-21),PR(Abcam,ab2764)和波形蛋白(Abcam,ab45939)。使用适宜的二抗(偶联有Alexa488或647)(Molecular probes)来检测结合的一抗。
Western印迹分析
将冷冻肿瘤称重,并在补充有蛋白酶抑制剂(F.Hoffman-La Roche,Ltd.,Germany),1mM苯基甲基磺酰氯,和磷酸酶抑制剂混合物1和2(Sigma,MO)的细胞提取物缓冲液(Invitrogen,CA)中用研棒PP(Scienceware,NJ)裂解。使用Pierce BCA蛋白质测定试剂盒(Rockford,IL)测定蛋白质浓度。对于Western印迹,通过电泳穿过NuPage Bis-Tris4-12%梯度凝胶(Invitrogen,CA)将等量的蛋白质分开,使用iBlot系统(Invitrogen,CA)将蛋白质转移到硝酸纤维素孔膜上。用于印迹的一抗包括pAkt(Ser473),pAkt(Thr308),总Akt,pS6(Ser235/236),pS6(Ser240/242)和总S6抗体(它们得自Cell Signaling Technology(Danvers,MA)),及抗肌动蛋白抗体(它购自Sigma-Aldrich(St.Louis,MO))。采用与适宜的偶联有的辣根过氧化物酶的IgG二抗结合的化学发光Western印迹检测(Amersham Biosciences,PA)来检测一抗结合的蛋白质。
药物功效研究
将乳腺肿瘤碎块皮下植入称重20-25g之间的8-10周雌性C.B-17SCID米色小鼠(Charles River Laboratories,MA)的乳腺脂肪垫附近。监测肿瘤,直至它们达到均值肿瘤体积200-300mm3,并将动物随机分入4组,每组9只动物,之后启动剂量给药。在含0.2%Tween80的0.5%甲基纤维素(MCT)媒介中溶解GDC-0941,并通过口服管饲法每天一次给药,持续13天,分三个剂量组:50,100和150mg/kg。在研究过程里每周两次记录肿瘤尺寸和小鼠体重。肿瘤体积用测径器以二维测量并用下述公式计算:肿瘤尺寸(mm3) =(长测量结果x短测量结果2)x0.5。使用下述公式计算百分比重量变化:组百分比重量变化=(新重量-初始重量)/初始重量)x100。计算均值肿瘤体积(+/-SEM)和百分比重量变化,并使用Kaleidagraph(4.03版,Synergy Software)绘制曲线图。根据IACUC指南,对肿瘤体积≥2,000mm3或相对于它们初始体重的体重损失≥20%的小鼠迅速处以安乐死。为了分析随时间来自同一动物的肿瘤体积的重复测量,使用一种混合建模办法(Pinheiro,J.,Bates,D.,DebRoy,S.,Sarkar,D.& The R Core team.nlme:Linear and Nonlinear Mixed Effects Models.R包3.1-89.版(2008))。这种办法解决重复测量和研究结束前动物的任何非治疗相关死亡所致的适度退出二者。使用三次回归样条将非线性曲线拟合每个剂量水平的log2肿瘤体积的时间过程。然后在混合模型内将这些非线性曲线与剂量联系起来。以相应每天剂量组与媒介相比的拟合曲线下面积(AUC)的百分数,计算媒介百分数(%TGI)形式的肿瘤生长抑制,这使用下述公式进行:%TGI=100x(1-AUC剂量/AUC媒介)。为了得到%TGI的不确定度区间(UI),使用拟合曲线和拟合协方差阵生成随机样本,作为%TGI分布的近似。随机样本由拟合-混合模型的1000次模拟实施构成,其中对每次实施重新计算%TGI。我们报告的UI是%TGI的重新计算值根据拟合模型有95%的机会会落在这个区域中的值。使用模拟分布的2.5和97.5百分位作为上和下UI。使用R(2.8.1版,R Development Core Team2008;R Foundation for Statistical Computing;Vienna,Austria)和Excel生成曲线图。使用R分析数据,并使用nlme包(Pinheiro et al.,见上文)在R内拟合混合模型。
结果
工程化改造可条件性激活的PIK3CA H1047R小鼠
为了研究PIK3CA突变在肿瘤启动,发生和发展中的作用,我们工程化改造小鼠能够条件性表达由其天然启动子驱动的突变型PIK3CA H1047R等位基因。工程化小鼠PIK3CAe20mwt具有经修饰含有侧翼loxP位点的野生型PIK3CA外显子20。经修饰野生型外显子后面是转录终止盒和一拷贝编码H1047R突变的PIK3CA外显子20(图1a-d)。使用打靶载体(图1b)修饰小鼠胚胎干(ES)细胞中的内源PIK3CA基因座。使用含有适宜修饰,通过Southern印迹鉴定(图1f,g)的两个独立ES细胞克隆生成显示PIK3CAe20mwt等位基因种系传递的嵌合小鼠。涉及杂合PIK3CAe20mwt/+小鼠的杂交以预期孟德尔比率 产生具有适宜基因型的后代(图13)。与PIK3CA-/-缺无小鼠(Bi,L.,Okabe,et al.,J Biol Chem274,10963-8(1999))中观察到的胚胎致死性不同,在Cre介导的重组之前,我们发现纯合PIK3CAe20mwt/e20mwt动物以预期孟德尔频率出生,指示经修饰PIK3CAe20mwt发挥与野生型PIK3CA等位基因类似的功能。
PIK3CAe20H1047R等位基因的乳腺特异性表达
由于PIK3CA在超过25%的人乳腺癌中是突变的(Zhao & Voigt,Oncogene27,5486-5496(2008)),通过将PIK3CAe20mwt小鼠与MMTV-Cre转基因小鼠(Wagner,K.U.et al.,Nucleic Acids Res25,4323-30(1997);Wagner,K.U.et al.,Transgenic Res10,545-53(2001))交配,我们测试PIK3CA H1047R在乳腺肿瘤发生中的作用。MMTV-Cre系在乳腺允许性MMTV LTR启动子控制下表达P1Cre重组酶,容许PIK3CAe20H1047R重组和表达。通过对与自PIK3CAe20H1047R/+小鼠乳腺提取的PIK3CA mRNA对应的cDNA测序,我们确认PIK3CAe20H1047R突变型等位基因和天然野生型PIK3CA等位基因的表达(图1h)。相反,自肾提取的RNA只显示来自PIK3CAe20mwt等位基因的野生型PIK3CA的表达(图1i),确认突变型PIK3CAe20H1047R等位基因的乳腺特异性表达。
PIK3CAe20H1047R的表达导致增强的乳腺分支形态发生
先前的研究显示癌基因的表达或肿瘤抑制基因(像PTEN)的丧失影响小鼠乳腺的分支和形态发生(Meyer,D.S.et al.,Cancer Research(2011);Li,G.et al.,Development129,4159-70(2002);Fishler,T.et al.,Oncogene29,4007-17(2010)。因此,我们使用全封固染色研究PIK3CAe20H1047R表达对乳腺发育的影响。在12周时,与对照乳腺中的正常末端终蕾(TEB)相比,PIK3CAe20H1047R突变型乳腺显示高度分支的导管和末端结构(图6a,b)。到第50周,与对照乳腺相比,PIK3CAe20H1047R突变型乳腺显示羽毛状的高度分支的形态(图6c,d)。而且,在50周龄时PIK3CAe20H1047R突变型乳腺的组织学切片显示肿瘤小结的证据(图6e,f)。这与涉及PTEN条件性缺无小鼠和具有PI3K途径激活的其它乳腺特异性转基因模型的先前研究(Meyer et al.,见上文;Li et al.,见上文)中报告的乳腺分支形态发生缺陷相似。
PIK3CAe20H1047R表达促进乳腺肿瘤发生
在80周时段里对雌性PIK3CAe20H1047R/+,PIK3CAe20mwt/+和MMTV-Cre小鼠跟踪乳腺肿瘤发生。我们发现杂合PIK3CAe20H1047R/+动物发生乳腺肿瘤(图 2a-c),中值无肿瘤存活478.5天。大多数动物在胸部乳腺中发生肿瘤(#1,2,3,6,7和8),而一些在腹股沟-腹部乳腺中发生肿瘤(#4,5,9和10),而且少数在胸部和腹股沟-腹部乳腺二者中发生肿瘤。与PIK3CAe20H1047R/+不同,对照PIK3CAe20mwt/+和MMTV-Cre动物在研究期间保持没有肿瘤。在自第二个独立靶定ES克隆衍生的PIK3CAe20H1047R/+小鼠中也观察到具有相似潜伏期的乳腺肿瘤表型(图2c),进一步确认PIK3CAe20H1047R表达驱动的肿瘤表型的特异性。
MMTV启动子在处女和哺乳乳腺中都驱动它控制下的基因的表达(Wagner,K.U.et al.,Nucleic Acids Res25,4323-30(2010))。因此,我们比较未产和经产小鼠中的肿瘤发生率,发现潜伏期在经产PIK3CAe20H1047R小鼠中与未产PIK3CAe20H1047R动物相比显著缩短(图7),从492天到465天(p=0.0002),提示妊娠相关乳腺变化有助于加速肿瘤发生。
虽然MMTV启动子自出生后第6天开始主要在乳腺上皮细胞中指导Cre表达,但是还知道它驱动唾液腺和雄性精囊中的表达(Wagner,K.U.et al.,Transgenic Res10,545-53(2001))。在实施来自携带乳腺肿瘤的小鼠的唾液腺和来自年龄在35-41周之间的雄性的精囊的组织学分析时,我们没有发现肿瘤的证据(图8a,b)。然而,与对照动物相比,PIK3CAe20H1047R/+小鼠(n=3)中的精囊在形态上更大。精囊横切片的组织学分析指示精囊液分泌量增多,导致导管膨胀和扩大(图8c,d)。然而,这不影响PIK3CAe20H1047R/+雄性的生育力和交配。
PIK3CAe20H1047R驱动的肿瘤中的组织学和信号传导激活
我们实施PIK3CAe20H1047R肿瘤的组织学分析以了解它的病理学特征,发现大多数肿瘤显示与纤维腺癌一致的特征(76.9%[20/26])(图2d),而少数显示腺癌(15.4%[4/26])(图2e,f)或纺锤细胞瘤形成(7.7%[2/26])(图2g)的组织病理学特征。
为了进一步表征肿瘤,我们测试组织学不同肿瘤类型的PI3K途径激活状态。在所有肿瘤类型中,我们观察到升高的pAKT和pS6激酶(图2h),二者都是PI3K的下游,指示这些肿瘤中该途径的组成性激活。
在进一步了解观察到的乳腺肿瘤类型的努力中,我们研究组织学不同乳腺肿瘤类型中基底细胞角蛋白5(CK5),内腔细胞角蛋白18(CK18),雌激素受体(ER),孕酮受体(PR),和波形蛋白(一种间充质标志物)的表达。 虽然我们发现纤维腺癌和腺癌都是CK5,CK18,ER和PR阳性的,都是纺锤细胞肿瘤是ER-/PR-(图3n,o)且CK5-的(数据未显示)。有趣的是,这让人回想起人乳腺纺锤细胞肿瘤也是ER/PR阴性。另外,纺锤细胞肿瘤是CK18+/波形蛋白+的(图3n,p),指示所述细胞正经历上皮-间充质转变(EMT)。
PIK3CAe20H1047R驱动的乳腺肿瘤的基因组分析
在实施PIK3CA H1047R乳腺肿瘤的基因组分析之前,鉴于肿瘤形成的长潜伏期,我们首先测试自乳腺肿瘤衍生的肿瘤外植体是否会像SCID小鼠中的异种移植物那样生长。测试的大多数纤维腺癌,腺癌和纺锤细胞肿瘤形成肿瘤。有趣的是,自纤维腺癌外植体衍生的肿瘤的组织学显示腺癌或纺锤细胞瘤形成的特征,指示纤维腺癌有可能是良性的且只是初始外植体内具有致瘤潜力的细胞子集有助于传代期间的肿瘤发生(图9a-d)。然而,纺锤细胞肿瘤外植体在传代期间维持它的组织学特征(图9e,f)。
我们实施不同乳腺肿瘤亚型和对照乳腺的基于微阵列的基因表达分析以进一步了解肿瘤的分子特征。使用上皮细胞,干细胞和EMT标志物的表达数据进行的分级聚簇(Weigelt,B.& Reis-Filho,Nature Reviews Clinical Oncology6,718-730(2009);Taube,J.H.et al.,Proceedings of the National Academy of Sciences107,15449-15454(2010))显示原代纤维腺癌,腺癌和来自这些肿瘤类型的外植体传代衍生的肿瘤聚簇在一起,指示一种共同的起源和共享的基因表达变化集合(图4a)。相反,纺锤细胞类型(原代和传代肿瘤二者)聚簇在一起,展示EMT的特征,提示一种不同的细胞起源(图4a)。
全外显子组捕捉和测序用于鉴定基因组的编码区中的体细胞突变(Varela,I.et al.,Nature469,539-542(2011))。为了了解在我们的模型中观察到的各种乳腺肿瘤类型中次要突变的出现,我们实施选定样品集合的全外显子组捕捉和测序(图14)。在工程化PIK3CA H1047R突变的存在之外,肿瘤还含有数种别的体细胞变化(表1)。我们发现纤维腺癌具有低水平的体细胞突变(介于2和5之间),接着是腺癌(22种突变)和纺锤细胞肿瘤(61种突变)。值得注意地,在纺锤细胞肿瘤中,我们鉴定出Trp53(TP53)中密码子245处Arg用His替换的突变(图4b)。这种突变等同于密码子248处的人TP53热点突变(R248H),而且是TP53的DNA结合域内已经充分表征的功能丧失性突变,使之作为显性负蛋白质(dominant negative protein)起作用 (Olivier,M.,Hollstein,M.& Hainaut,P.,Cold Spring Harbor Perspectives in Biology2,a001008-a001008(2010))。而且,TP53突变和原代纺锤细胞肿瘤中鉴定的大多数突变也见于传代后的外植体衍生肿瘤,指示原代纺锤肿瘤有可能杂合性较低(图10)。正如在纺锤细胞肿瘤中观察到的,原代腺癌中存在的大多数突变存在于移植后衍生的肿瘤中(图10)。在腺癌中,在观察到的22种突变中,12种(包括Plk1,Tssk2,和SMG1激酶中的突变)预测具有功能效果,因此可能作为驱动器起作用(表1和图10)。有趣的是,人乳腺癌中的SMG1突变先前已有报告(Stephens,P.et al.,Nature Genetics37,590-592(2005))。
在全外显子组突变分析之外,我们在CGH阵列上测定肿瘤的概况以了解染色体拷贝数改变。有趣的是,反映在纤维腺癌和腺癌中观察到的低水平的体细胞突变,这两种肿瘤类型都具有很少区域的拷贝数异常。与纤维腺癌和腺癌形成对比,在纺锤细胞肿瘤样品中,我们发现与正常乳腺相比具有拷贝数改变的数个区域。我们观察到染色体11中一个~3Mb区域的广泛扩增和染色体1和4中的局灶性增益。更多详情参见Yuan W.et al.,Oncogene(2012),1-9,包括Oncogene网站(http://www.nature.com/onc)上伴随该论文的补充信息,它们都通过述及明确收入本文。纺锤细胞肿瘤也表征为落在染色体11和12内的两个区域的染色体丢失,二者都含有数种编码基因。特别地,染色体11中的删除导致Nf1丧失(图4C),而且与它下调的表达一致(log2比率-2.09;p=8.338e-05,图4A),提示Ras-MAPK途径可能也参与这些肿瘤。
PIK3CAe20H1047R乳腺肿瘤响应PI3K抑制剂
遗传工程化小鼠模型为临床前背景中的候选药物测试提供理想平台(Singh,M.et al.,Nat Biotechnol28,585-93(2010))。由于这项研究中的小鼠在长潜伏期后发生乳腺肿瘤,我们使用我们的肿瘤外植体衍生肿瘤模型来测试它在评估药物功效中的效用。将自具有TP53突变的纺锤细胞肿瘤衍生的外植体皮下植入乳腺脂肪垫附近,并一旦肿瘤达到至少~200mm3就用PI3KCA抑制剂GDC-0941(Edgar,K.A.et al.,Cancer Research70,1164-1172(2010);Folkes,A.et al.,WO2007127175)进行治疗。分4组(每组9只动物)用50,100和150mg/kg GDC-0941或媒介处理荷瘤小鼠。我们发现用GDC-0941处理的动物显示最高的肿瘤生长抑制(TGI),150mg/kg为85%,尽管与媒介处理相比在测试的其它剂量也观察到肿瘤生长抑制(图5a),指 示这些肿瘤的生长仍然依赖于突变型PIK3CA信号传导。而且,这些进展前时间数据的时序检验显示与媒介对照处理动物相比,所有药物治疗组在测试的所有剂量显示统计学显著差异(150mg/kg的p<0.0001;图12)。与观察到的TGI一致,来自用GDC-0941治疗的小鼠的肿瘤显示pAKT和pS6的显著降低,至少延续至治疗后10小时(图5b),确认PI3K抑制在肿瘤生长抑制中的贡献。
讨论
癌症的遗传工程化小鼠模型对于了解肿瘤启动,进展和治疗评估是无价的(Tuveson,D.& Hanahan,D.,Nature471,316-7(2011))。另外,将下一代测序技术应用于这些模型能提供关于肿瘤发展期间发生的分子异常的有价值信息。在此,我们描述乳腺癌的可条件性激活的PIK3CA H1047R小鼠模型,并显示这些小鼠发生多种组织学类型的乳腺肿瘤,包括纤维腺癌,腺癌和纺锤细胞瘤形成。我们发现腺癌对于激素受体和细胞角蛋白(CK5+/CK18+)是阳性的,指示它们是上皮起源的。相反,虽然纺锤细胞肿瘤是细胞角蛋白18阳性的,但是区别在于它们是ER/PR阴性的,但波形蛋白阳性的。这让人回想起人乳腺纺锤肿瘤(Khan,H.,European Journal of Surgical Oncology29,600-603(2003);Carter,M.R.,et al.,Am J Surg Pathol 30,300-9(2006))。在我们的乳腺癌模型中观察到的多种组织学类型与先前涉及小鼠中PIK3CA H1047R驱动乳腺癌的转基因模型的研究一致(Adams,J.R.et al.,Cancer Research71,2706-2717(2011);Meyer,D.S.et al.,Cancer Research(2011))。然而,我们的模型中乳腺肿瘤发生的潜伏期与PIK3CA H1047R突变型cDNA在使用MMT-Cre激活其表达后在ROSA26基因座启动子(中值存活,A系为150天;NLST系>500天)或鸡β-肌动蛋白启动子(平均214±22.6天)控制下表达的两项研究相比更长。这有可能反映下述事实,即我们的敲入模型自其以其正常基因组构造存在的内源启动子表达突变型PIK3CA等位基因,因此更加精确地模拟体内PIK3CA H1047R驱动的肿瘤发生。
下一代测序技术的出现容许在序列水平综合表征癌症(Stratton,M.R.,et al.,Nature458,719-724(2009))。在应用下一代测序技术时,我们表征了自我们的小鼠模型衍生的肿瘤以了解PIK3CA H1047R突变型等位基因表达后乳腺肿瘤发生所需要的别的打击。在可能与PIK3CAH1047R合作的数种候 选次要打击中,我们报告纺锤细胞肿瘤中TP53R245H突变的发生。R245H突变等同于在人癌症中观察到的R248H热点显性-负突变型。功能丧失性TP53R245H突变的自发出现,TP53突变与PIK3CA突变在乳腺癌中共发生的事实(Boyault,S.et al.,Breast Cancer Research and Treatment(2011))及TP53丧失在转基因小鼠模型中显示与致癌性PIK3CA合作(Adams,J.R.et al.,Cancer Research71,2706-2717(2011))提示这有可能是合作性驱动突变。这指示我们的模型模拟有助于人乳腺肿瘤发生的损伤,因此会是研究突变型PIK3CA驱动的乳腺肿瘤中的治疗性干预的理想模型。据此,我们演示该模型的效用,即在具有EMT特征的乳腺肿瘤子集中测试PI3K抑制剂GDC-0941的功效。一份先前的报告在PIK3CA H1047R转基因肺肿瘤模型中研究双重泛PI3K和哺乳动物雷帕霉素靶物(mTOR)抑制剂NVP-BEZ235的功效。然而,鉴于PIK3CA突变在人乳腺癌中更加频繁,我们的模型可充当遗传限定系统来测试PI3K抑制剂在乳腺癌中的功效及潜在帮助模拟用于临床药物测试的治疗方案。
除了在研究乳腺肿瘤发生中的效用之外,通过使用适宜的组织特异性Cre系激活突变型PIK3CA等位基因,该模型还可用于研究已经观察到PIK3CA突变的其它癌症。而且,该模型与下一代测序技术结合可用于发现和了解在别的肿瘤类型中与突变型PIK3CA合作的其它驱动基因。鉴于已经将PI3K途径激活与对治疗的抗性联系起来,PI3KCA H1047R小鼠还可用于模拟药物抗性及研究治疗策略以克服抗性。
Claims (41)
1.一种非人转基因动物,其包含经修饰内源PIK3CA基因座,其中所述经修饰内源PIK3CA基因座包含与野生型外显子20相邻的编码H1047R的休眠突变型PIK3CA外显子20,且其中所述非人转基因动物能够进行PIK3CA H1047R(PIK3CAe20H1047R)突变型等位基因的条件性表达。
2.权利要求1的非人转基因动物,其中所述突变型等位基因的条件性表达处于PIK3CA内源启动子控制之下。
3.权利要求3的非人转基因动物,其中所述条件性表达是由所述突变型等位基因通过Cre介导的重组的激活触发的。
4.权利要求1的非人转基因动物,其中所述条件性表达是组织特异性的。
5.权利要求4的非人转基因动物,其中所述条件性表达是乳腺特异性的。
6.权利要求1的非人转基因动物,其中所述条件性表达导致突变型PIK3CAH1047R表达和肿瘤发生。
7.权利要求1至6任一项的非人转基因动物,其为啮齿类动物。
8.权利要求7的非人转基因动物,其为小鼠或大鼠。
9.一种荷瘤非人转基因动物,其条件性表达处于PIK3CA内源启动子控制之下PIK3CA H1047R(PIK3CAe20H1047R)突变型等位基因。
10.权利要求9的荷瘤非人转基因动物,其以组织特异性方式表达PIK3CAH1047R突变型等位基因。
11.权利要求10的荷瘤非人转基因动物,其中所述PIK3CA H1047R突变型等位基因在所述动物的乳腺中表达且所述肿瘤是乳腺肿瘤。
12.权利要求11的荷瘤非人转基因动物,其对于PIK3CA H1047R突变型等位基因是杂合的。
13.权利要求11的荷瘤非人转基因动物,其对于PIK3CA H1047R突变型等位基因是纯合的。
14.权利要求11的荷瘤非人转基因动物,其中所述乳腺肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
15.权利要求9的荷瘤非人转基因动物,其为啮齿类动物。
16.权利要求15的荷瘤非人转基因动物,其为小鼠或大鼠。
17.一种用于生成权利要求1的转基因动物的方法,其包括放置一拷贝编码H1047R突变的外显子20,与编码野生型PIK3CA等位基因的外显子20相邻。
18.权利要求17的方法,其中所述编码野生型PIK3CA等位基因的外显子20侧翼为lexP位点,接着是转录终止盒和一拷贝编码H1047R突变的PIK3CA外显子20。
19.一种对受试者筛选肿瘤存在情况的方法,该方法包括对自所述受试者获得的生物学样品测试PIK3CA H1047R等位基因或相应基因产物的存在情况。
20.权利要求19的方法,其中所述肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
21.权利要求19的方法,其中所述肿瘤选自下组:乳腺癌,卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌,子宫内膜癌,白血病和中枢神经系统恶性肿瘤。
22.权利要求21的方法,其中所述肿瘤为乳腺癌。
23.权利要求19的方法,其进一步包括对所述样品测试次要体细胞突变的存在情况或拷贝数改变。
24.权利要求23的方法,其中所述次要体细胞突变在TP53基因中。
25.权利要求24的方法,其中所述次要体细胞突变为R248H,A135V或I195NTP53突变。
26.权利要求25的方法,其中所述次要体细胞突变为R248H TP53突变。
27.权利要求23的方法,其中所述次要体细胞突变在Plk1,Tssk2或SMG1基因中。
28.一种筛选用于治疗肿瘤的药物候选物的方法,其包括(a)将药物候选物施用于权利要求9的荷瘤非人动物,并(b)测量所述肿瘤对所述治疗的响应。
29.权利要求28的方法,其中步骤(b)包括评估所述药物候选物引起至少一种选自下组的响应的能力:减少肿瘤细胞数目,缩小肿瘤尺寸或肿瘤负荷,抑制肿瘤细胞浸润入周围器官,抑制肿瘤转移,和抑制肿瘤生长。
30.权利要求28的方法,其中所述肿瘤选自下组:纤维腺癌,腺癌和纺锤细胞瘤形成。
31.权利要求28的方法,其中所述肿瘤选自下组:乳腺癌,卵巢癌,结肠直肠癌,胃癌,肺癌,肝细胞癌,甲状腺癌,子宫内膜癌,白血病和中枢神经系统恶性肿瘤。
32.权利要求31的方法,其中所述肿瘤为乳腺癌。
33.权利要求28的方法,其中所述药物候选物为小分子,肽,多肽,或抗体。
34.权利要求33的方法,其中所述药物候选物为抗体。
35.一种鉴定用于治疗药物抗性癌症的抗癌剂的方法,其包括(a)将药物候选物施用于权利要求9的荷瘤非人动物,(b)测量所述肿瘤对所述治疗的响应,并(c)若所述肿瘤对所述治疗展现正面响应,则将所述药物候选物鉴定为用于治疗药物抗性癌症的抗癌剂。
36.权利要求35的方法,其中所述正面响应选自下组:减少肿瘤细胞数目,缩小肿瘤尺寸或肿瘤负荷,抑制肿瘤细胞浸润入周围器官,抑制肿瘤转移,和抑制肿瘤生长。
37.一种用于鉴定PI3K抑制剂的方法,其包括(a)将PI13K抑制剂候选物施用于权利要求9的荷瘤非人动物,(b)测量所述肿瘤对所述治疗的响应,并(c)若所述肿瘤对所述治疗展现正面响应,则将所述候选物鉴定为PI13K抑制剂。
38.权利要求37的方法,其中所述癌症为乳腺癌。
39.权利要求9的荷瘤非人动物在筛选用于治疗肿瘤的药物候选物的方法中的用途,其包括(a)将药物候选物施用于权利要求9的荷瘤非人动物,并(b)测量所述肿瘤对所述治疗的响应。
40.权利要求9的荷瘤非人动物在鉴定用于治疗药物抗性癌症的抗癌剂的方法中的用途,其包括(a)将药物候选物施用于权利要求9的荷瘤非人动物,(b)测量所述肿瘤对所述治疗的响应,并(c)若所述肿瘤对所述治疗展现正面响应,则将所述药物候选物鉴定为用于治疗药物抗性癌症的抗癌剂。
41.权利要求9的荷瘤非人动物在用于鉴定PI3K抑制剂的方法中的用途,其包括(a)将PI13K抑制剂候选物施用于所述荷瘤动物,(b)测量所述肿瘤对所述治疗的响应,并(c)若所述肿瘤对所述治疗展现正面响应,则将所述候选物鉴定为PI13K抑制剂。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107828786A (zh) * | 2017-10-24 | 2018-03-23 | 昆明理工大学 | 靶向敲除PIK3CA基因的sgRNA及应用 |
CN108471732A (zh) * | 2015-10-30 | 2018-08-31 | 杰克逊实验室 | 与肿瘤分析相关的组合物和方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2948351C (en) * | 2014-05-09 | 2023-10-03 | Memorial Sloan-Kettering Cancer Center | Biomarkers for response to pi3k inhibitors |
CA2985894A1 (en) | 2015-05-15 | 2016-11-24 | Memorial Sloan-Kettering Cancer Center | Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations |
RU2608960C1 (ru) * | 2016-03-18 | 2017-01-27 | Федеральное государственное бюджетное учреждение "Российский онкологический научный центр имени Н.Н. Блохина" Министерства здравоохранения Российской Федерации (ФГБУ "РОНЦ им. Н.Н. Блохина" Минздрава России) | Клеточная линия crov Cel муцинозного рака яичников человека, предназначенная для разработки лечения таргетными препаратами |
BR112021015353A2 (pt) | 2019-02-06 | 2021-10-05 | Venthera, Inc. | Inibidores de fosfoinositídeo 3-cinase tópicos |
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005091849A2 (en) * | 2004-03-02 | 2005-10-06 | The Johns Hopkins University | Mutations of the pik3ca gene in human cancers |
EP1978106A1 (en) * | 2007-04-07 | 2008-10-08 | Universitätsklinikum Hamburg-Eppendorf | Detection of ESR1 amplification in endometrium cancer and ovary cancer |
CN101445832A (zh) * | 2008-12-23 | 2009-06-03 | 广州益善生物技术有限公司 | Pik3ca基因突变的检测探针、液相芯片及其检测方法 |
CN101715345A (zh) * | 2007-04-10 | 2010-05-26 | 埃克塞里艾克西斯公司 | 使用吡啶并嘧啶酮PI3Kα抑制剂的治疗方法 |
CN101939429A (zh) * | 2007-12-03 | 2011-01-05 | 桑塔里斯制药公司 | 用于调节pik3ca表达的rna拮抗剂化合物 |
US20110060605A1 (en) * | 2009-09-09 | 2011-03-10 | Quintiles Transnational Corp. | Methods for predicting responsiveness of a disease or disorder to a receptor tyrosine kinase inhibitor by analysis of mutations in pik3ca |
CN102105474A (zh) * | 2008-05-30 | 2011-06-22 | 健泰科生物技术公司 | 嘌呤pi3k抑制剂化合物及使用方法 |
JP2011121944A (ja) * | 2009-12-11 | 2011-06-23 | Wyeth Llc | ホスファチジルイノシトール−3−キナーゼ経路バイオマーカー |
WO2011087926A1 (en) * | 2010-01-13 | 2011-07-21 | Wyeth Llc | A CUT-POINT IN PTEN PROTEIN EXPRESSION THAT ACCURATELY IDENTIFIES TUMORS AND IS PREDICTIVE OF DRUG RESPONSE TO A PAN-ErbB INHIBITOR |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP2402347A1 (en) | 2006-04-26 | 2012-01-04 | F. Hoffmann-La Roche AG | Pharmaceutical compounds |
WO2011060380A1 (en) * | 2009-11-14 | 2011-05-19 | The Regents Of The University Of California | Pik3ca mutation status and sash1 expression predicts synergy between lapatinib and an akt inhibitor in her2 positive breast cancer |
-
2012
- 2012-07-26 EP EP12748281.8A patent/EP2736325B1/en active Active
- 2012-07-26 JP JP2014522813A patent/JP2014529298A/ja active Pending
- 2012-07-26 MX MX2014001063A patent/MX2014001063A/es unknown
- 2012-07-26 RU RU2014107713/10A patent/RU2014107713A/ru not_active Application Discontinuation
- 2012-07-26 CN CN201280046858.0A patent/CN104010494B/zh active Active
- 2012-07-26 WO PCT/US2012/000336 patent/WO2013015833A2/en active Application Filing
- 2012-07-26 BR BR112014002121A patent/BR112014002121A2/pt not_active IP Right Cessation
- 2012-07-26 KR KR1020147004811A patent/KR20140050689A/ko not_active Application Discontinuation
- 2012-07-26 US US14/233,976 patent/US20140298493A1/en not_active Abandoned
- 2012-07-26 CA CA2843222A patent/CA2843222A1/en not_active Abandoned
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005091849A2 (en) * | 2004-03-02 | 2005-10-06 | The Johns Hopkins University | Mutations of the pik3ca gene in human cancers |
EP1978106A1 (en) * | 2007-04-07 | 2008-10-08 | Universitätsklinikum Hamburg-Eppendorf | Detection of ESR1 amplification in endometrium cancer and ovary cancer |
CN101715345A (zh) * | 2007-04-10 | 2010-05-26 | 埃克塞里艾克西斯公司 | 使用吡啶并嘧啶酮PI3Kα抑制剂的治疗方法 |
CN101939429A (zh) * | 2007-12-03 | 2011-01-05 | 桑塔里斯制药公司 | 用于调节pik3ca表达的rna拮抗剂化合物 |
CN102105474A (zh) * | 2008-05-30 | 2011-06-22 | 健泰科生物技术公司 | 嘌呤pi3k抑制剂化合物及使用方法 |
CN101445832A (zh) * | 2008-12-23 | 2009-06-03 | 广州益善生物技术有限公司 | Pik3ca基因突变的检测探针、液相芯片及其检测方法 |
US20110060605A1 (en) * | 2009-09-09 | 2011-03-10 | Quintiles Transnational Corp. | Methods for predicting responsiveness of a disease or disorder to a receptor tyrosine kinase inhibitor by analysis of mutations in pik3ca |
JP2011121944A (ja) * | 2009-12-11 | 2011-06-23 | Wyeth Llc | ホスファチジルイノシトール−3−キナーゼ経路バイオマーカー |
WO2011087926A1 (en) * | 2010-01-13 | 2011-07-21 | Wyeth Llc | A CUT-POINT IN PTEN PROTEIN EXPRESSION THAT ACCURATELY IDENTIFIES TUMORS AND IS PREDICTIVE OF DRUG RESPONSE TO A PAN-ErbB INHIBITOR |
Non-Patent Citations (1)
Title |
---|
JESSICA R. ADAMS 等: ""Cooperation between Pik3ca and p53 Mutations in Mouse Mammary Tumor Formation"", 《CANCER RESEARCH》, vol. 71, no. 7, 1 April 2011 (2011-04-01), pages 2706 - 2717, XP002687640, DOI: 10.1158/0008-5472.CAN-10-0738 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108471732A (zh) * | 2015-10-30 | 2018-08-31 | 杰克逊实验室 | 与肿瘤分析相关的组合物和方法 |
CN107828786A (zh) * | 2017-10-24 | 2018-03-23 | 昆明理工大学 | 靶向敲除PIK3CA基因的sgRNA及应用 |
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US20140298493A1 (en) | 2014-10-02 |
MX2014001063A (es) | 2014-09-01 |
EP2736325A2 (en) | 2014-06-04 |
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WO2013015833A3 (en) | 2013-09-26 |
JP2014529298A (ja) | 2014-11-06 |
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WO2013015833A2 (en) | 2013-01-31 |
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RU2014107713A (ru) | 2015-09-10 |
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