多发性骨髓瘤的转化医学研究-课件

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styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title styleText Line 2,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,多发性骨髓瘤的转化医学研究,多发性骨髓瘤的转化医学研究,VCAM-1,Fibronectin,ICAM-1,LFA-1,MUC-1,VLA-4,Cytokines,IL-6, VEGF,IGF-1, SDF-1,BAFF, APRIL,BSF-3,TNF,TGF,VEGF,NF-,B,NF-,B,BMSC,adhesion,molecules,NF-,B,Smad, ERK,JAK/STAT3,MEK/ERK,PI3-K,GSK-3,FKHR,Caspase-9,NF-B,mTOR,Bad,PKC,Bcl-xL,Mcl-1,MEK/ERK,p27,Kip1,NF-B,Bcl-xL,IAP,Cyclin-D,MM,Survival,Anti-apoptosis,Cell cycle,Survival,Anti-apoptosis,Cell cycle,proliferation,Survival,Anti-apoptosis,Akt,migration,Proliferation,Anti-apoptosis,cytokines,Raf,FGFR3,Adhesion,骨髓微环境与骨髓瘤细胞的,生长、生存和耐药,Hideshima T and Anderson KC、 Nat Rev Cancer 2007,SC,CD40,CS1,BAFF-R,Cell surface,targets,VEGFR,VCAM-1ICAM-1LFA-1MUC-1VLA-4Cyt,1962,1983,1986,1996,1999,2000+,二膦酸盐,口服马法兰,+,泼尼松,VAD,大剂量地塞米松,自体干细胞支持下的大剂量化疗,蛋白酶体抑制剂,新一代免疫调节剂,多发性骨髓瘤治疗的发展史,大剂量马法兰,1984,沙利度胺,ABMT,196219831986199619992000+二膦酸盐口,硼替佐米:从实验室到临床的快速转化,I,期临床试验,2000,靶向于骨髓瘤细胞和骨髓微环境,能克服体内外耐药,针对难治复发骨髓瘤开展了,II,期临床试验,2003,获,FDA,批准:,CR,率,35%,中位反应持续时间,12,个月,III,期临床试验:与地塞米松比较,治疗复发骨髓瘤,FDA,批准其用于难治性骨髓瘤:硼替佐米延长,TTP,和,OS,2006,新的蛋白酶体抑制剂和联合用药方案,作为一线治疗,有特别高的总反应率和,CR,率,2008,FDA,批准硼替佐米为,MM,一线治疗用药,2010,研究发现硼替佐米在,MM,巩固和维持治疗中有效,硼替佐米:从实验室到临床的快速转化,Bortezomib,JNK; Caspases ,ROS;, ,m,Cyto-c ,IAPs;,mitochondrial Ca,+2,influx;,Bid cleavage, Fas & FasL, BH-3 only proteins: Bim, Bik, & NOXA,凋亡,Migration, VEGF,Proangiogenic MMP-9, &,Caveolin-1;,Osteoclastogenesis,via,MIP1, BAFF,Osteoblast formation,抗新生血管形成,&,抑制破骨细胞活性,Caspase-12 cleavage;,phospo-PERK;,GADD-153, ATF4, GRP 78, &,XBP-1 splicing,诱导内质网应激,Cdk inhibitors:,P21 & p27,p53,Cyclins: D1, E1, A, B.,细胞周期,MM-BMSCs interaction;,ICAM, VCAM,V,3,IGF-1, IL-6, BAFF,RANKL,微环境,NF-,B, MAPK,JAK/STAT,IGF-1/IL-6.,PI3K-Akt,生长,&,生存,Heat Shock Proteins-27, -70, 90;,DNA-PK,热休克蛋白,& DNA,损伤修复,Chymotrypsin- and Caspase- like proteasome activities;,Mono-ubiquitination;, 26S,Proteasome subunits,作用于蛋白酶体,硼替佐米的抗骨髓瘤作用机制,Bortezomib JNK; Caspases & P,1998-2000,:,Len,作用于骨髓瘤细胞,(,通过,caspase-8,促进凋亡,),及骨髓微环境,2001,:,I,期临床试验,最大耐受剂量为,25mg,毒副作用不大,79%,的患者,SD,2002,:三个,II,期试验肯定了其疗效和耐受性;,Dex,能提高,Len,的,ORR,2006,:针对复发,MM,的,III,期临床试验表明,Len+Dex,优于安慰剂,+Dex,(,OR,CR,TTP,OS),获,FDA,批准,2009,:针对复发和新诊断的,MM,的,13,项,II-III,期临床试验表明,Len+Bort+Dex,联用获得较好的,ORR,2012,:,III,期临床试验,Len,能延长自体移植患者的,PFS,和,OS,2013,:,III,期临床试验,用,Len+Dex,直至,PD,能延长,PFS,和,OS,来那度胺:从实验研究到临床应用,1998-2000:Len作用于骨髓瘤细胞(通过caspas,来那度胺治疗骨髓瘤的作用机制,MM cells,Bone Marrow Stromal Cells,Dendritic,Cells,IL-6,TNF,IL-1,A,IL-2,IFN,CD8+ T Cells,C,E,Bone Marrow Vessels,ICAM-1,VEGF,bFGF,D,B,NK Cells,NK-T Cells,Hideshima et al、 Blood 96: 2943, 2000,Davies et al、 Blood 98: 210, 2001,Gupta et al、 Leukemia 15: 1950, 2001,Mitsiades et al、 Blood 99: 4525, 2002,Lentzsch et al Cancer Res 62: 2300, 2002,LeBlanc R et al、 Blood 103: 1787, 2004,Hayashi T et al、 Brit J Hematol 128: 192, 2005,PKC,NFAT,PI3K,IL-2,CD28,来那度胺治疗骨髓瘤的作用机制MM cellsBone Mar,新发现的免疫调节剂作用机制,Kronke et al, Science, 2014 Lu et al, Science,2014,新发现的免疫调节剂作用机制Kronke et al, Sci,Stewart AK, Richardson PG, San Miguel JF,Blood,2009,联合用药方案应用于骨髓瘤一线治疗,Stewart AK, Richardson PG, San,20S,20S,19S,19S,a,b,5,5i,1,1i,2,2i,ATPases/,Cdc48,Potential,Therapeutic Targets,26S PROTEASOME,ATP,ADP,UB enzymes E1, E2 and,E3-UB-Ligases,Ub,Ub,Ub,Poly-ubiquitinated proteins,(proteasome substrates),Free,for re-cycling,Six Protease,activities,Degraded protein,Ub,Immunoproteasome,针对蛋白酶体的新药,Deubiquitylating,Enzymes (DUBs),Bortezomib,Carfilzomib,CEP-18770,ONYX-0912,MLN 2238,NPI-0052:,5,1,2,5,PR-924,Targeting USP-7,USP14/UCHL 15,20S20S19S19Sab5, 5iATPases/P,蛋白酶体抑制剂的作用机制是调节,NF-kB,？,多种肿瘤,NF-kB,活性升高,为何,MM,效果特别好？,为何,NF-kB,抑制剂对骨髓瘤细胞的抑制不如万珂？,蛋白酶体抑制剂的作用机制是调节NF-kB？多种肿瘤NF-kB,骨髓瘤细胞的软肋,骨髓瘤患者血清,M,蛋白能够超过,100g/l (AFP,是以,g,/l,为单位的,),骨髓瘤细胞每分钟能够分泌,10000,至,80000,个,M,蛋白分子,其中,1/4,至,1/3,估计发生错误折叠,未折叠或错误折叠的蛋白能够导致细胞凋亡,骨髓瘤细胞的软肋骨髓瘤患者血清M蛋白能够超过100g/l (,Protein,protein aggregates,(toxic),Ub,Ub,Ub,Ub,26S proteasome,Ub,Ub,Ub,Ub,Ub,Aggresome,Panibinostat,Vorinostat, ACY1215,dynein,Ub,Ub,dynein,Microtubule,Autophagy,Bortezomib, Carfilzomib, NPI0052,MLN9708, ONX 0912,Ub,Ub,Ub,Lysosome,HDAC6,HDAC6,HDAC6,Ub,Ub,研究合理的联合治疗方案,(,联合,HDAC),Hideshima et al、,Clin Cancer Res,、 2005;11:8530、Catley et al、,Blood,、 2006;108:3441-9、,Proteinprotein aggregatesUbUbU,Vorinostat,治疗复发难治,MM,VANTAGE 088:,国际多中心随机双盲研究,比较,Vorinostat,或安慰剂联合硼替佐米,治疗复发难治,MM,Vorinostat+,硼替佐米组对复发难治患者有效,显著提高治疗反应率:,ORR 54% vs 41%(,P,0、0001);CBR 71% vs 53%(,P,0、0001),联合用药组的,PFS,、,TTP,比安慰剂,+,硼替佐米组更长,PFS,风险比(,hazard ratio,)下降了,23%(,P,=0、01),两组的,PFS,分别为,7、63,月,(6、98、4),、,6、83,月,(5、77、7),最常见的,3-4,级不良事件为(,vorinostat,组,vs,安慰剂组):血小板减少,(45% vs 24%),中性粒细胞减少,(28% vs 25%),贫血,(17% vs 13%,Dimopoulos et al Lancet Oncol,2013; 14: 1129-40、,Vorinostat治疗复发难治MMVANTAGE 088:,Panobinostat,治疗复发难治,MM,PANORAMA 1,随机双盲,II,期临床试验,比较,Panobinostat,或安慰剂,+,硼替佐米、地塞米松治疗复发难治,MM,中位,PFS,延长,4,月,ORR,、,OS,无显著差异,nCR/CR,率增加,2,倍,(28% vs 16%),以下毒副作用发生率在,PAN-BTZ-Dex,组较高:,3,、,4,级腹泻,(25、5% vs 8%),疲乏,(23、0% vs 11、9%),血小板减少,(67、4% vs 31、4%),白细胞减少,(34、5% vs 11、4%),因急性事件导致治疗中断的发生率,(33、6% vs 17、3%)、,PANORAMA 2,PAN-BTZ-Dex,方案对既往反复治疗过的、对硼替佐米耐药的,MM,患者的疗效:,ORR 34、5%; CBR 52、7%;,中位,PFS:,5、4,月,;,中位,OS: 17、5,月,1,2,有必要接着寻找毒性小但选择性更高的,HDACi,Richardson PG, et al、 Blood、 2013;122:2331-2337,Richardson PG et al、 Blood 2013; 122:Abstract 1970,Panobinostat治疗复发难治MMPANORAMA 1,EARLY,LATE,Early mutationnot in late sample,New mutations in late sample,Early Tumor,Late Tumor,全基因组测序发现,MM,进展过程中获得新的分子生物学异常,Early Tumor,Late Tumor,Bolli et al, Nature m 2014,EARLY LATE Early mut,骨髓瘤基因组演化及克隆演变,No Change,Differential Clonal Response,Linear Evolution,Branching Evolution,Bolli et al, Nature m, 2014,骨髓瘤基因组演化及克隆演变No ChangeDifferen,正在研究中的靶向治疗药物,BTK inhibitors,KSP inhibitors (Array 520),AKT inhibitor,Nuclear transport inhibitors (KPT),CDK inhibitors,Bromodomain inhibitors,正在研究中的靶向治疗药物BTK inhibitors,抗体介导的细胞依赖的细胞毒作用,(ADCC),ADCC,Effector cells:,MM,FcR,