1、 从分子水平对疾病的重新认识从分子水平对疾病的重新认识 不断提高的诊断技术和不断积累的临床实践不断提高的诊断技术和不断积累的临床实践 将来的肿瘤治疗模式：以分子生物学诊断为基础的综将来的肿瘤治疗模式：以分子生物学诊断为基础的综合性靶向治疗合性靶向治疗对疾病的进一步认识:分子生物学的创立引起肿瘤治疗模式的变化肿瘤部位（实体）肿瘤部位（实体）肿瘤组织肿瘤组织分子生物学分子生物学肿瘤的基因类型肿瘤的基因类型HER tyrosine-kinase inhibitorsApoptosisRas signalingVEGF signallingHER signalingTPApoptotic agents
2、Farnesyl-transferaseinhibitorsAnti-HER1 /2 MAbsTumor-activatedchemotherapyAnti-VEGF MAbsVEGF-R tyrosine kinase inhibitors1-2 mmAngiogenic SwitchSmall tumor Nonvascular “Dormant”Larger tumor Vascular Metastatic potentialTumor CellSoluble FactorsVEGFPDGFFGFEtc.Growth FactorsEGFCOX2Etc.HIF1a aRECMInteg
3、rinsMMPsAdapted from Poon RT, et al. J Clin Oncol 2001;19:120725新生血管生成在肿瘤发展过程的不同阶段所扮演的角色恶变前期恶变前期恶性肿瘤恶性肿瘤肿瘤生长肿瘤生长血管侵袭血管侵袭微转移处于微转移处于休眠状态休眠状态明显的转移明显的转移(肿瘤无血管肿瘤无血管)(血管新生开始血管新生开始)(肿瘤形成血管肿瘤形成血管)(肿瘤细胞进入血管内肿瘤细胞进入血管内)(远道种植远道种植)(再次形成新生血管再次形成新生血管)新生血管生成参与肿瘤形成生长转移的全程Tumour angiogenesisTumour4. Appearance of new
4、 tumour vasculature1. Secretion ofangiogenicfactors3. Endothelial cell proliferation and migration2. Proteolyticdestruction of extracellular matrixSprouting capillary2000200020012001200220022003200320042004200520052006200620072007美罗华美罗华 MabTheraMabThera 希罗达希罗达 XelodaXeloda 赫赛汀赫赛汀 HerceptinHerceptin
5、格列卫格列卫 GlivecGlivec 易瑞沙易瑞沙 IressaIressa 特罗凯特罗凯 TarcevaTarceva 爱必妥爱必妥 ErbituxErbitux 恩度恩度EndostatinAvastinPhase IPhase IIPhase IIIApprovedGefitinibTarcevaAZD2171BortezomibVandetanibMotesanibSorafenibAvastinMatuzumabCetuximabBexaroteneImatinibAZD6244TipifarnibTalabostatPF-3512676CelecoxibSunitinibAS14
6、04VEGF TRAPLapatinibRAD001CP-751871ABT-751VatalanibPanitumumabAngiogenesis inhibitorsEGFR/HER inhibitorsOther molecular-targeted therapiesHKI-272Anti- HER2/neuAnti- HER2/neu 赫赛汀赫赛汀 (Herceptin(Herceptin ) )基质金属蛋白酶抑制剂基质金属蛋白酶抑制剂蛋白酶体抑制剂蛋白酶体抑制剂 Bortezomib(Velcade Bortezomib(Velcade ) )Anti-CD 20Anti-CD 2
7、0 美罗华美罗华 (Rituxan(Rituxan ) )PDGF-RPDGF-R抑制剂抑制剂 格列卫格列卫 (Glivec (Glivec ) )SRCSRC激酶抑制剂激酶抑制剂Aurora Aurora 激酶抑制剂激酶抑制剂MEK (MEK (信号传导信号传导) )抑制剂抑制剂 CI-1040CI-1040 全人源单抗全人源单抗 tumumab tumumab (Vectibix)Vectibix)EGFR IgG2EGFR IgG2单抗单抗可与CD20特异结合的鼠源可变区人源恒定区人源IgG1的Fc片断研究 方案 N 有效率% 中位持续时间 CR PR RR 随访时间 有效时间 TTPJ
8、aeger etal CHOP+Riruximab巩固 41 90 10 100 24.3 NR NRSWOG9800 同上 84 54 18 72 NR NR NRM39023 MCP/R-MCP 106 40 41 81 NR NR NRGregory et al FM+Rituximab 31 45 52 97 NR NR NRM39005 HDT+PBSCT 28 55 45 100 NR NR NR研究 方案 N 有效率% 中位持续时间 CR PR OS 随访时间 有效时间 TTP102-10/U0715s 联合CHOP 33 76 18 94 31 NR NRLNH98-5 联合C
9、HOP 202 82 11 93 NR NR NRNCI/MGH/UM 联合EPOCH 20 85 0 85 12 NR NRNCI/MGH/UM 联合EPOCH 14 64 21 85UHZ 联合EPOCH 39 23 46 69 12 NR NR初治复发难治CD52CD22CD30CD25CD20CD80CD40HLA-DR以细胞表面抗原及受体为靶点的单抗以细胞间微环境为新靶点 Avastin Thalidomi以细胞内调节蛋白及信号通路为新靶点 G3139 CCI-779抗CD20单抗：Rituximab (创多项第一) （FDA1998 SDA2000）抗CD22单抗：Epratzum
10、ab抗CD52单抗：Campath-1H（2001）抗CD25单抗 Ontak（1999） 抗CD30单抗 5F11 SGN31抗CD4单抗 Zanolimumab 可与VEGF特异结合的鼠源可变区人源IgG1的Fc片断N813CPT-11 125mg/m2 d1、8、155-FU 500mg/m2 d1、8、15LV 20mg/m2 d1、8、15安慰剂 每6周为一周期CPT-11 125mg/m2 d1、8、155-FU 500mg/m2 d1、8、15LV 20mg/m2 d1、8、15AVASTIN 5mg/kg 每两周一次每6周为一周期安慰剂组 AVASTIN组 P病例数中位生存（月
11、）风险比中位无进展生存（月）风险比总有效率中位有效时间（月）41115.66.4357.140220.3.6610.6.544510.40.0010.0010.01N=1045-FU 500mg/m2LV 500mg/m2每周一次连用6周每8周重复5-FU 500mg/m2LV 500mg/m2AVASTIN 5mg/kg/2w5-FU 500mg/m2LV 500mg/m2AVASTIN 10mg/kg/2w5-FU/LV AVASTIN 5mg/kg 10mg/kg病例数中位总生存（月）中位无进展生存（月）总有效率3613.65.2173517.79.0403315.27.224Modif
12、ied from: Kowanetz and Ferrara. Clin Cancer Res. 2006;12:5018-5022.EPC RecruitmentMigrationInvasionProliferation SurvivalMigrationPermeabilityLymphangiogenesisVasculogenesisVEGFR-3VEGFR-2VEGFR-1MAPKMEKPKCAkt/PKBAkteNOSPI3-KSrcIMC-18F1BevacizumabVEGF-TrapIMC-1121bSunitinibVatalanibMotesanibAxitinibAZ
13、D2171PazopanibSunitinibVatalanibSorafenibVandetanibMotesanibAxitinibAZD2171PazopanibSunitinibSorafenibVandetanibMotesanibAxitinibAZD2171PazopanibmTORTemsirolimusEverolimus化疗与化疗与Herceptin的疗效比较的疗效比较 EGFVEGFVEGFMabVEGF EGF and theirCombinations EU6!, KHAvastinMabIressaTarcevaAZDTK inhibitor CetuximabCu
14、nningham D, et al. N Engl J Med. 2004;351:337-345.PRPR10.8%10.8%22.9%22.9%.0074.0074TTPTTP1.5 1.5 个月个月4.14.1个月个月.0001.0001总生存期总生存期6.96.9个月个月8.68.6个月个月NSNSBOND 结果 BOND 研究研究: 爱必妥爱必妥 + 伊立替康伊立替康 (n=218)Cunningham D Van Cutsem E. N Engl J Med 2004Cetuximab + FOLFOX-4400 mg/m2 initial IV infusion (day 1)t
15、hen 250 mg/m2 weekly+ oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeksFOLFOX-4 oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeksEGFR-expressing metastatic CRCStratification factors: ECOG PS 0-1, 2RTreatment until progression, symptomatic deterioration or unacceptable toxicity* Cochran-Mantel-Haenszel (CMH) t
16、estOdds ratio = 1.516, p=0.064*35.781.045.685.20102030405060708090ORRDCRpercentage patients, % FOLFOX-4 Cetuximab + FOLFOX-4*Cochran-Mantel-Haenszel (CMH) test1366.753.242.201020304050607080Grade 0Grade 1Grade 2Grade 3-4*Overall response rate (%)Cetuximab + FOLFOX-4, n=168 (IRC data)n=23n=59n=62n=24
17、Maximum skin reactions during first 21 days of treatment*There were no grade 4 skin reactions12010080604020细胞相对数0.00010.0010.010.11.010药物浓度N=425 试验39（既往接受过至少2周期含铂类方案化疗） 试验16（既往最多接受过2周期化疗至少一周期含铂类方案化疗）250mg/d500mg/d250mg/d500mg/d 试验39 试验16250mg/d 500mg/d 250mg/d 500mg/d有效率%缓解时间中位疾病控制时间中位PSF中位生存11.8174
18、.11.96.18.8243.62.06.018.4153.22.7NC19.0164.62.8NC1. Wilhelm S, Chien DS. Curr Pharm Des 2002;8:225522572. Chang YS, et al. Clin Cancer Res 2005;11:9011S Wilhelm SM, et al. Cancer Res 2004;64:7099109 Wilhelm SM, et al. Cancer Res 2004;64:7099109 Sorafenib400 mg bidn=451Placebon=452Primary endpoints
19、Survival (alpha=0.04) PFS (alpha=0.01)(1:1) Randomizationn= 903Stratification CountryEligibility criteria Confirmed, advanced disease Clear-cell histology Measurable disease Failed one prior systemic therapy in last 8 months Low/intermediate risk MSKCC groups included ECOG PS 0 or 1 Good organ funct
20、ion No brain metastasisStudy DesignProportion of patients progression free00.250.500.751.00Time from randomization (weeks)0612182436486066Median PFS*Sorafenib = 24 weeksPlacebo = 12 weeksHazard ratio = 0.44p-value 0.00000154Censored observationPlaceboSorafenibEscudier B et al. Oral presentation, ASC
21、O, 2005 *Independently assessed *PFS analysis performed March, 2005 (data cut-off Jan 28, 2005)Escudier B et al. Oral presentation, ECCO 13, 2005 *At 220 events, May 31, 2005 *OBrien-Fleming stopping boundary for significance was p0.0005PlaceboCensored observationSorafenibMedian OSSorafenib = Not re
22、achedPlacebo = 14.7 months Hazard ratio = 0.72p-value = 0.018*Time from randomization (months)0410202681214161800.250.500.751.00Overall survival索拉非尼组索拉非尼组400mg 2次次/天天n=299安慰剂组安慰剂组n=303入选条件：入选条件：l 晚期晚期HCCl ChildPugh A 级级l ECOG PS 02l 预期生存预期生存12 月月主要终点lOS lTTSP随机化随机化Llovet JM, et al. ASCO 2007, Chicag
23、o, IL, USAECOG PS = 东部肿瘤协作组体力状态; OS = 总生存; TTSP = 症状进展时间; TTP = 疾病进展时间中位总体生存时间中位总体生存时间:OS*索拉菲尼组 = 46.3 周 (10.7 个月)安慰剂组 = 34.4 周 (7.9 个月)危险比 = 0.69 (95% CI: 0.550.88)P = 0.000580 8 16 24 32 40 48 56 64 72 80 时间（周）时间（周）1.000.750.500.25 0索拉菲尼组索拉菲尼组安慰剂组安慰剂组总总体体生生存存率率*有统计学意义的有统计学意义的OBrienFleming检验水准界值为检验
24、水准界值为 p=0.0077；CI =可信区间可信区间Llovet J, et al. ASCO 2007, Chicago, USA1.000.750.500.25 00 6 12 18 24 30 36 42 48 54时间（周）时间（周）无疾病进展生存率索拉菲尼组索拉菲尼组安慰剂组安慰剂组中位疾病进展时间中位疾病进展时间:TTP索拉菲尼组 = 24.0 周 (5.5 个月)安慰剂组 = 12.3 周 (2.8 个月)危险比 = 0.58 (95% CI: 0.450.74)P = 0.000007Llovet J, et al. ASCO 2007, Chicago, USALlovet
25、 J, et al. ASCO 2007, Chicago, USATrials of Angiogenesis Inhibitors in NSCLCPPPPPP核酪氨酸激酶受体作用机制配体结合部位与ATP结合部位酪氨酸激酶接触反应区ATPPGlivecN1027慢性期532例(干扰素治疗失败)400mg/天加速期235例400600mg/天急变期260例400600mg/天慢性期 加速期 急变期血液学缓解率完全血液学缓解率退回慢性期细胞遗传学缓解率完全缓解部分缓解88%(84.9-90.6)88-49(45.1-53.8)301963%(56.5-69.2) 282421%(16.2-27
26、.1)14 726%(20.9-31.9)41913.5(9.6-18.2)58.5% 147例不能切除或转移的c-kit+患者400mg/天进展600mg/天600mg/天进展出组45403530252015105病人4019139126PR SD PD UNK部分缓解病变稳定不确定性的PR肿瘤消退26-49其它SD病变进展不祥Flk-1 shown to be VEGF-R(Millauer et al., Quinn et al.) Dominant negative VEGFR-2Inhibits tumor angiogenesis and-grwoth in vivo(Millau
27、er et al.) 1993 1994 1999 2003 2006SU5416 inhibits tumor growthIn vivo (Fong et al.)SU11248 orally activemulti-targeted drug (OFarrell et al.)SUTENT approval by FDAand EMEA (Pfizer)RCC pathogenesis and progression VEGF PDGFVascularpermeabilityCell survival, proliferation, migrationVascularformation,
28、 maturationLoss of VHL protein functionVEGFPDGF VEGFRPDGFRVascular endothelial cellPericyte/fibroblast/vascular smooth muscleSunitinib同时同时抑制多抑制多种种 RTKs 表表达达： 不同的不同的肿瘤肿瘤細胞細胞 血管血管內皮細胞內皮細胞双通道双通道抑制抑制肿瘤的生长肿瘤的生长 抑制肿瘤细胞的生长抑制肿瘤细胞的生长抑制肿瘤抑制肿瘤血管血管的生成的生成Sunitinib malate：多：多 种种RTKs強力抑制強力抑制在約在約40 種激酶的測試中，種激酶的測試中，sunitinib malate 顯示有強力且具目標選擇性顯示有強力且具目標選擇性的活性的活性HER1EGFRHER2HER3HER4HER-2nucleuscancer cellcell divisionTrastuzumab (Herceptin) Anti-HER-2 Antibody (IV)Lapatinib (Tykerb) Dual HER-1/HER-2 (oral) Tyrosine Kinase InhibitorLancet Oncol 2006，7: 282
