侯健-多发性骨髓瘤转化医学研究

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Title,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,Presented by:,*,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 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,*,*,多发性骨髓瘤的转化医学研究,第二军医大学长征医院血液科,全军骨髓瘤与淋巴瘤疾病中心,侯 健,Translational Medicine: from bench to bedside,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,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,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，有很高的总反应率和,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,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,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,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,新发现的免疫调节剂作用机制,Kronke et al, Science, 2014 Lu et al, Science,2014,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,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,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？,骨髓瘤细胞的软肋,骨髓瘤患者血清,M,蛋白可以超过,100g/l (AFP,是以,g,/l,为单位的,),骨髓瘤细胞每分钟可以分泌,10000,至,80000,个,M,蛋白分子,其中,1/4,至,1/3,可能发生错误折叠,未折叠或错误折叠的蛋白可以导致细胞凋亡,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.,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 Onc