酪氨酸激酶(课堂PPT).ppt

TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,*,GLI-PM1651/01-11-2007TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,Text sentence caps,Second level,Third level,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,*,GLI-PM1651/01-11-2007,TITLES 30PT ARIAL BOLD TITLE CASE SUBTITLES 28PT ABOVE LINE LINE,mm,.,Fourth level,Fifth level,肿瘤与酪氨酸激酶,March 11,2014,概述,肿瘤是一种常见且多发病，而恶性肿瘤目前正极大的危胁着人类的健康，当今生命科学中抗肿瘤研究成为极富挑战性且意义重大的领域。,研发的焦点正在从传统细胞毒性药物转移到针对肿瘤细胞内异常信号系统靶点的特异性抗肿瘤药物。,传统细胞毒药物,选择性差,、,毒副作用强,、,易产生耐药性,等特点，而靶点特异性抗肿瘤药针对于正常细胞和肿瘤细胞之间的差异，达到了,高选择性,、,低毒性、特异性强,的治疗效果。,March 11,2014,March 11,2014,蛋白酪氨酸激酶,(tyrosine kinase,）,蛋白酪氨酸激酶是一类具有酪氨酸激酶活性的蛋白质，可分为受体型和非受体型，其功能都是催化,ATP,的磷酸基转移到下游蛋白的酪氨酸,(Tyr)残基上，使其发生磷酸化。,在细胞信号转导通路中占据十分重要的地位，调节着细胞的生长、分化、死亡等一系列生理生化过程。,超过,50,的原癌基因和癌基因产物都是酪氨酸激酶，它们的异常表达通常导致细胞增殖调节发生紊乱，致使肿瘤发生。,与肿瘤的侵袭、转移、肿瘤新生血管生成以及肿瘤的化疗抗药性密切相关。,March 11,2014,超过20个不同家族的,受体型,酪氨酸激酶被作为靶标进行抗肿瘤药物筛选，包括表皮生长,因,子受体(EGFR)、血管内皮细胞生长因子受体(V,E,GFR)、血小板衍生生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)、胰岛素受体(InsR),等。,受体型酪氨酸激酶（tyrosine kinase,）,酪氨酸激酶受体,恶性肿瘤或骨髓增生紊乱,EGFR,（,ErbB1,）,非小细胞肺癌，头颈部肿瘤，结肠癌，胰腺癌,HER-2/neu(ErbB2),乳腺癌，卵巢癌，头颈部肿瘤,PDGFR,高嗜酸性粒细胞综合征，肥大细胞症，胃肠道间质瘤,FGFR3,膀胱癌，多发性骨髓瘤,c-KIT,胃肠道间质瘤，系统性肥大细胞增生,FLT-3,急性髓系白血病,RET,2,型多发性内分泌腺瘤，家族性髓样甲状腺瘤,c-MET,肝细胞肿瘤，黑色素瘤，胶质母细胞瘤，上皮性恶性肿瘤,March 11,2014,ATP,ADP,ATP,ADP,P,P,底物蛋白,底物蛋白,P,胞外,胞内,酪氨酸激酶蛋白,酪氨酸激酶蛋白,March 11,2014,EGFR,曲妥珠单抗,靶向原癌基因人表皮生长因子受体,-2,（,Her-2,）的重组人源化单克隆抗体，由,Genentech,公司开发。,1998,年,10,月在美国首次上市，用于治疗转移性乳腺癌。本品可改变,Her-2,阳性乳腺癌的自然病程。,用于胃肠癌、,NSCLC,、膀胱癌、胰腺癌等治疗处于,期临床研究中,。,不良反应：,March 11,2014,吉非替尼,(gefitinib,）,选择性,EGFR-TK,抑制剂，由阿斯利康公司开发。,2002,年,7,月在日本首次上市，用于治疗非小细胞肺癌,(NSCLC,）是首个获准上市的,EGFR-TK,抑制剂，属于苯胺喹哪唑啉化合物，为小分子靶向抗肿瘤药物。,用于前列腺癌、食管癌、肝细胞癌,(HCC),、胰腺癌、膀胱癌、肾细胞癌,(RCC),、卵巢癌、头颈部癌、恶性黑色素瘤。,本品最常见不良反应是痤疮样皮疹和腹泻，最严重不良反应是间质性肺病，发生率为,3,-5,。,March 11,2014,伊马替尼,(Imatinib),结构,：是一种,2-,苯胺嘧啶衍生物，是首个小分子酪氨酸激酶抑制剂。,机理,：,1),抑制,Bcr-Abl,治疗慢性髓细胞白血病,(CML),；,2),抑制,KIT,治疗胃肠道间质瘤,(GIST),，使,KIT,激酶失活，抑制细胞生长，导致细胞凋亡或,/,和细胞死亡；,3),抑制血小板衍生生长因子受体,(PDGFRA),，,GIST,有,PDGFRA,突变者有效。,生物利用度,：与治疗,CML,同，胃肠道已切除者仍可达治,疗血药浓度。,March 11,2014,KIT 受体酪氨酸激酶的正常生理功能,造血,皮肤色素,生育,肠运动,(,节律形成细胞,),增殖,分化,凋亡,/,存活,粘附,/,趋化,KIT,功能获得性突变导致,GIST,的发生，黑素细胞功能失调和皮肤肥大细胞增生,KIT,对以下过程具有重要作用,1,KIT,的激活对以下功能非常重要，包括,1,March 11,2014,P,P,P,P,ATP,表达,伊马替尼,激酶区,伊马替尼抑制,KIT,信号通路,KIT,激酶的,ATP,结合,口袋被伊马替尼占据,底物磷酸化被阻断和,信号通路被抑制,伴随着信号抑制，增殖,和存活被阻断,March 11,2014,伊马替尼现状,可能的毒副反应为,:,水肿、白细胞减少、乏力、腹痛、恶心、呕吐、肌肉痉挛、皮疹、肝肾功能损害、出血等。,伊马替尼治疗,GIST,的成功已经成为分子靶向药物治疗肿瘤的典范。,尽管,GIST,患者对伊马替尼有较高的反应率及良好耐受性，,但仍有,20%,的患者对伊马替尼原发耐药。而继发耐药出现于用药,1,年后，主要是由于,C-kit,或者,PDGFR,激酶发生了再次突变、基因扩增或靶点酪氨酸激酶表达缺失等原因。,患者对伊马替尼耐药比例也不断提高,成为临床治疗,G IST,一个棘手的问题。,伊马替尼面临问题,March 11,2014,舒尼替尼,舒尼替尼（,Sunitinib,）,的问世一定程度解决了这一难题。,舒尼替尼是一种新型多受体酪氨酸激酶抑制剂,可以通过抑制,KIT,、,PDGFR,、,VEGFR,、集落刺激因子,1,受体等信号转导途径达到抗肿瘤和抗血管生成的效应。,2006,年,2,月,FDA,批准本品用于治疗进展期,RCC,和胃肠道间质肿瘤,(GIST,）本品可切断肿瘤细胞生长的血液和营养供应，同时还可直接杀伤肿瘤细胞，且未见一般化疗的常见毒副作用。,March 11,2014,舒尼替尼作用机制,March 11,2014,舒尼替尼的临床研究,在随机对照双盲研究,NCT00075218,中评价了舒尼替尼治疗和伊马替尼治疗失败或不能耐受的,GIST,患者疗效,结果显示,接受舒尼替尼治疗的,GIST,患者的肿瘤缓解、肿瘤控制率和中位疾病进展时间均优于对照组,显示舒尼替尼可作为对伊马替尼耐药的,GIST,患者的二线治疗用药。,March 11,2014,小 结,C-kit,原癌基因和血小板起源生长因子受体,(PDGFRA),基因突变是,GIST,发生的关键因素。,Imatinib,是第一个成功治疗,GIST,有效靶向药物。,舒尼替尼已成为格列卫耐药后的一线药物。,待深入研究问题尚多，期待国内多中心协作试验。,March 11,2014,谢 谢！,