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1、结肠癌的分子靶向治疗 哪些靶点？ David GoldsteinConjoint Professor UNSW Prince of Wales Hospital关于靶点 背景 化疗 抗血管生成 细胞内二级信使 新的方向细胞通路信息给我们提供许多潜在的治疗靶点WNTCellsECMGrowth factors (e.g. EGF, amphiregulin TGF-a)Nuclear receptors (e.g. oestrogen)Survival factors (e.g. IGF1)Cytokines (e.g. ILs, IFNs)Death factors (e.g. FasL)An
2、ti-growth factors (e.g. TGF-b)Hormones (e.g. bombesin)FrizzledDisheveledGSK-3bAPCTubulinTCFIntegrinsb-Cateninb-Catenin:TCFE-CadherinCdC42PI3KRacFakCasCrkSrcFyn ShcNF1RasRTKGrb2 SOSRalMEKMAPKMAPKMEKKPLCPKCMosMKKsJNKsELKMyc:MaxMax:MaxFosJUNAbl7-TMRCdC42RacRhoG-ProlAd CyclPKACREBPKCNF-kBNHR (e.g. ER)NF
3、-kBP13KAktAkkaIKBPTEN?Stat 3.5Stat 3.5Stat 3.5Bcl XLCaspase 9Cytochrome CJaksBadBidMitochondriaBim, etc.Abnormality sensorBcl 2Cell death (Apoptosis)Caspase 8FAPFADDBcl 2BaxARFp53MitochondriaMDM2DNA damage sensorCell proliferation (cell cycle)Changes in gene expressionCycl E:CDK2p21p27E2FsRbp16Cycl
4、D:CDK4p15SmadsRTKCytokine RFasSurface AgTGFbRHPVE7Decoy RHanahan D and Weinberg RA Cell 2000Hanahan D and Weinberg RA Cell 2000老药新用哪种联联合化疗疗方案是有效的 FOLFOX 奥沙利铂 ERCC1, TS levels 关于外周血多态性和肿瘤基因表达水平的研究 166 例连续患者 Folfox 4 ERCC1 and XPD SNPS in PBCs, 与预后相关的表型研究Ruzzo A JCO 2007哪种联联合化疗疗方案是有效的 伊利替康 拓扑异构酶1和TS的表
5、达 培美曲塞伊利替康和FOLFIRI的治疗临床试验 (Underhill et al Oncology 2008) 随机入组130例, 66例有原发灶样本 TS/DPD/TOPO1均未发现有显著的预后预测价 值。 TS和MTHFR（亚甲基四氢叶酸还原酶）的单链 核苷酸多态性也未发现有显著的预后预测价值 。Braun, M. S. et al. J Clin Oncol; 26:2690-2698 2008Fig 2. CONSORT diagram值值得关注的研究11个对对CPT-11和LOHP治疗疗效果可能有价值值的预测预测 分子 6个分子标记标记 物采用免疫组组化的方法进进行评评估: ex
6、cision repair cross-complementing gene 1 (ERCC1); Topoisomerase-1 (Topo1) p53 O-6-methylguanine-DNA-methyltranserase (MGMT) cyclooxygenase 2 (COX2), 错错配修复基因的免疫组组化评评估 (MLH1/MSH2 有四个基因评评估其基因的单链单链 核苷酸多态态性: Glutathione-S-transferase-P1 (GSTP1) A313G ATP-binding-cassette-group-B, gene 1 (ABCB1) x-ray-cro
7、ss-complementing-group 1 (XRCC1) Q399R ERCC2 K751Q. UGT1A1*28基因的多种串连连重复的启动动子多态态性评评估Braun, M. S. et al. J Clin Oncol; 26:2690-2698 2008Fig 3. 不同治疗疗策略的总总生存以及TOPO1的表达情况combinationsequentialMAX Study AGITG Tebbutt NSargeant D ASCO 2008MSI is a positive prognostic marker6 randomised trials of 5FU vs No R
8、x, data pooled, 10-19% dMMRMSI status is a predictive factor for 5FU化疗疗的靶点 ERCC或者TOPO1的表达水平可能是预测化 疗有效性的靶点 寻找能够预测 需要接受单药治疗或联合化疗 的靶点 MSI状态 临床指标 WCC, LDH, sites of metastases Kohne et alNew TargetsMay receive bevacizumab pastdisease progressionMay receive bevacizumab pastdisease progressionNo bevacizum
9、ab past diseaseprogressionIFL bevacizumab的III期临床研究:IFL:bolus 5-FU 500mg/m2leucovorin 20mg/m2irinotecan 125mg/m2given 4/6 weeksBolus IFL + bevacizumab (n=402)Previously untreated metastatic CRC5-FU/LV + bevacizumab (n=110)Bolus IFL + placebo (n=411)5-FU/LV:bolus 5-FU 500mg/m2 leucovorin 500mg/m2 give
10、n 6/8 weeksBevacizumab: 5mg/kg every 2 weeksHurwitz H, et al. NEJM 2005生存Kabbinavar, F. F. et al. J Clin Oncol; 23:3706-3712 2005Fig 2. SurvivalGiantonio, B. J. et al. J Clin Oncol; 25:1539-1544 2007Fig 2. BEVACIZUMAB + FOLFOX 4在既往治疗过疗过 的结结直肠肠癌患者中的疗疗效 Kaplan-Meier estimates of progression-free survi
11、val (PFS)Folfox/Bev Folfox BevGiantonio, B. J. et al. J Clin Oncol; 25:1539-1544 2007BEVACIZUMAB + FOLFOX 4 IN PREVIOUSLY TREATED COLORECTAL CANCERFolfox 4 + BevFolfox 4BevHochster, H. S. et al. J Clin Oncol; 26:3523-3529 2008TREE Studies Oxali/5FU +/_ Bevacizumab Fig 2. Kaplan-Meier plots of overal
12、l survival150 pts223 ptsMST 18.2 moMST 23.7 moORR +BevCapeox 20 37Folfox 41 52bFOL 27 46TTPCapox 5.9 10.3Folfox 8.7 9.9bFOL 6.9 8.3Cassidy J ASCO 2007Cassidy, J. et al. J Clin Oncol; 26:2006-2012 2008Fig 4. Overall survival (intent-to-treat population ITT)Saltz, L. B. et al. J Clin Oncol; 26:2013-20
13、19 2008Fig 2. Progression-free survival (intent to treat population)Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008Fig 3. Overall survival (intent to treat population)1.00.80.60.40.20 05101520253035MonthsSurvival estimateNo treatment (n=253) No Avastin post PD (n=531) Avastin post PD (n=642)Post
14、-progression therapy:12.619.931.8BRiTE registry study: 肿瘤进展后再次使用贝伐单抗的 生存获益Post-progression Avastin HR=0.48 (0.410.57) p0.001Grothey, et al. ASCO 2007VEGF 一个有价值的靶点 与化疗药物联合应用 哪些患者适合采用？ 无预测价值的分子标记物 可溶性VEGFR水平单药治疗 影像学 MRI/CT和功能性超声检查Median overall survival in first-line metastatic CRCBest supportive care
15、06121824Median overall survival (months)46 months1214 months5-FU/LV1920 monthsFOLFOX4 or CAPEOX1516 monthsIFL or FOLFIRI20.6 monthsFOLFOX6 FOLFIRI 18.3 months5-FU/LV + bevacizumab25.1 monthsIFL + BV OX20.3 monthsIFL + bevacizumabMetastasisProliferation/MaturationSurvival/ApoptosisAngiogenesisMAPKMEK
16、Gene transcription Cell-cycle progressionPI3-KRASRAFSOSGRB2PTENAKTSTATpYpYKK pYEGFR Signal TransductionMG1SG2Baselga J EGFR Blockade3rd Line2nd Line1st LineVan Cutsem E J Clin Oncol 2007Panitumumab在结肠癌中的三线治疗Van Cutsem, E. et al. J Clin Oncol; 25:1658-1664 2007Fig 2. Progression-free survival (all randomly assigned analysis set)NCIC CTG CO.17: Randomized Phase
