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1、结肠癌的分子靶向治疗 哪些靶点？ David Goldstein Conjoint 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,WNT,Cells,ECM,Growth 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
2、.g. FasL),Anti-growth factors (e.g. TGF-b),Hormones (e.g. bombesin),Frizzled,Disheveled,GSK-3b,APC,Tubulin,TCF,Integrins,b-Catenin,b-Catenin:TCF,E-Cadherin,CdC42,PI3K,Rac,Fak,Cas,Crk,Src,Fyn,Shc,NF1,Ras,RTK,Grb2,SOS,Ral,MEK,MAPK,MAPK,MEKK,PLC,PKC,Mos,MKKs,JNKs,ELK,Myc:Max,Max:Max,Fos,JUN,Abl,7-TMR,C
3、dC42,Rac,Rho,G-Prol,Ad Cycl,PKA,CREB,PKC,NF-kB,NHR (e.g. ER),NF-kB,P13K,Akt,Akka,IKB,PTEN,?,Stat 3.5,Stat 3.5,Stat 3.5,Bcl XL,Caspase 9,Cytochrome C,Jaks,Bad,Bid,Mitochondria,Bim, etc.,Abnormality sensor,Bcl 2,Cell death (Apoptosis),Caspase 8,FAP,FADD,Bcl 2,Bax,ARF,p53,Mitochondria,MDM2,DNA damage s
4、ensor,Cell proliferation (cell cycle),Changes in gene expression,Cycl E:CDK2,p21,p27,E2Fs,Rb,p16,Cycl D:CDK4,p15,Smads,RTK,Cytokine R,Fas,Surface Ag,TGFbR,HPVE7,Decoy R,Hanahan D and Weinberg RA Cell 2000,Hanahan D and Weinberg RA Cell 2000,老药新用,哪种联合化疗方案是有效的,FOLFOX 奥沙利铂 ERCC1, TS levels 关于外周血多态性和肿瘤基
5、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,哪种联合化疗方案是有效的,伊利替康 拓扑异构酶1和TS的表达 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
6、:2690-2698 2008,Fig 2. CONSORT diagram,值得关注的研究,11个对CPT-11和LOHP治疗效果可能有价值的预测分子 6个分子标记物采用免疫组化的方法进行评估: excision repair cross-complementing gene 1 (ERCC1); Topoisomerase-1 (Topo1) p53 O-6-methylguanine-DNA-methyltranserase (MGMT) cyclooxygenase 2 (COX2), 错配修复基因的免疫组化评估 (MLH1/MSH2 有四个基因评估其基因的单链核苷酸多态性: Glut
7、athione-S-transferase-P1 (GSTP1) A313G ATP-binding-cassette-group-B, gene 1 (ABCB1) x-ray-cross-complementing-group 1 (XRCC1) Q399R ERCC2 K751Q. UGT1A1*28基因的多种串连重复的启动子多态性评估,Braun, M. S. et al. J Clin Oncol; 26:2690-2698 2008,Fig 3. 不同治疗策略的总生存以及TOPO1的表达情况,combination,sequential,MAX Study AGITG Tebbut
8、t N,Sargeant D ASCO 2008,MSI is a positive prognostic marker,6 randomised trials of 5FU vs No Rx, data pooled, 10-19% dMMR,MSI status is a predictive factor for 5FU,化疗的靶点,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 al,New Targets,May receive
9、 bevacizumab past disease progression,May receive bevacizumab past disease progression,No bevacizumab past disease progression,IFL bevacizumab的III期临床研究:,IFL: bolus 5-FU 500mg/m2 leucovorin 20mg/m2 irinotecan 125mg/m2 given 4/6 weeks,Bolus IFL + bevacizumab (n=402),Previously untreated metastatic CRC
10、,5-FU/LV + bevacizumab (n=110),Bolus IFL + placebo (n=411),5-FU/LV: bolus 5-FU 500mg/m2 leucovorin 500mg/m2 given 6/8 weeks,Bevacizumab: 5mg/kg every 2 weeks,Hurwitz H, et al. NEJM 2005,生存,Kabbinavar, F. F. et al. J Clin Oncol; 23:3706-3712 2005,Fig 2. Survival,Giantonio, B. J. et al. J Clin Oncol;
11、25:1539-1544 2007,Fig 2. BEVACIZUMAB + FOLFOX 4在既往治疗过的结直肠癌患者中的疗效 Kaplan-Meier estimates of progression-free survival (PFS),Folfox/Bev Folfox Bev,Giantonio, B. J. et al. J Clin Oncol; 25:1539-1544 2007,BEVACIZUMAB + FOLFOX 4 IN PREVIOUSLY TREATED COLORECTAL CANCER,Folfox 4 + Bev Folfox 4 Bev,Hochster
12、, H. S. et al. J Clin Oncol; 26:3523-3529 2008,TREE Studies Oxali/5FU +/_ Bevacizumab Fig 2. Kaplan-Meier plots of overall survival,150 pts,223 pts,MST 18.2 mo,MST 23.7 mo,ORR +Bev Capeox 20 37 Folfox 41 52 bFOL 27 46 TTP Capox 5.9 10.3 Folfox 8.7 9.9 bFOL 6.9 8.3,Cassidy J ASCO 2007,Cassidy, J. et
13、al. J Clin Oncol; 26:2006-2012 2008,Fig 4. Overall survival (intent-to-treat population ITT),Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008,Fig 2. Progression-free survival (intent to treat population),Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008,Fig 3. Overall survival (intent to treat
14、population),1.0 0.8 0.6 0.4 0.2 0,0 5 10 15 20 25 30 35,Months,Survival estimate,No treatment (n=253) No Avastin post PD (n=531) Avastin post PD (n=642),Post-progression therapy:,12.6,19.9,31.8,BRiTE 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) p0.001,Grothey, et al
15、. ASCO 2007,VEGF,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 CRC,Best supportive care,0,6,12,18,24,Median overall survival (months),46 months,EGFR Signal Transduction,Baselga J,EGFR Blockade 3rd Line 2nd Line 1st Line,Va
16、n Cutsem E J Clin Oncol 2007,Panitumumab在结肠癌中的三线治疗,Van Cutsem, E. et al. J Clin Oncol; 25:1658-1664 2007,Fig 2. Progression-free survival (all randomly assigned analysis set),NCIC CTG CO.17: Randomized Phase III Trial in mCRC,EGFR testing by IHC,* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV week
17、ly,Disease Progression or Unacceptable Toxicity,REGISTER,RANDOMI ZE,1:1,Cetuximab* + BSC,BSC alone,Failed or intolerant to all recommended therapies, ECOG 0-2, No Prior EGFR directed therapy,Primary Endpoint: Overall Survival Secondary Endpoints: Progression Free Survival Objective Response Rate (RE
18、CIST criteria) Safety and Quality of Life,NCIC CTG CO.17: Progression Free Survival,CETUXIMAB + BSC,CENSORED,BSC,CENSORED,Proportion Progression-Free,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,MONTHS,0,3,6,9,12,15,HR 0.68 (95% CI =0.57 0.80) Stratified log rank p-value 0.0001,Jonker et al , NEJM 20
19、07,CETUXIMAB + BSC,CENSORED,BSC,CENSORED,NCIC CTG CO.17: Overall Survival,HR 0.77 (95% CI =0.64 0.92) Stratified log rank p-value = 0.0046,Jonker et al , NEJM 2007,Sobrero, A. F. et al. J Clin Oncol; 26:2311-2319 2008,EPIC Study Second Line Phase III, Oxaliplatin Progression,HR 0.97,HR 0.692,转移性结直肠癌
20、一线治疗 Phase III Folfiri +/- Cetuximab 在EGFR（）的结直肠癌,N=1217 患者 PFS 8.9 vs 8.0 months, HR 0.851 p=0.047 1 year PFS 23% vs 34% RR 46.9 vs 38.7% 根治性手术的增加 2.5 to 6% OR 3.0 肝转移灶完全消失 9.8 vs 4.5%,哪些人将采用 EGFRI治疗?,一个新的靶点?,EGFR Signaling Cascade and K-ras,Akt,SOS,FOS Myc,P13K,FKHR,mTOR,PTEN,MEK 1/2,MAPK,BAD,GSK-
21、3,Shc,Grb-2,Ras,Raf,Jun,p27,Cyclin D-1,Ligand,Signal Adapters and Enzymes,Signal Cascade,EGFR dimer,Transcription Factors,STAT,K-ras is a small G protein Self inactivating from GDP to GTP state Switched off by intrinsic GTPase activity K-ras mutation leads to constitutive activation mediated through
22、 reduced GTPase activity Inhibitors upstream may be ineffective,Randomization stratification ECOG score: 0-1 vs. 2 Geographic region: Western EU vs. Central & Eastern EU vs. Rest of World,1:1,Hypothesis: The treatment effect of panitumumab monotherapy is larger in patients with wild-type k-RAS compa
23、red to patients with mutant k-RAS,KRAS analysis of panitumumab vs BSC,Van Cutsem, Peeters et al. JCO. 2007;25:1658-1664.,Amado et al. JCO 2008,K-RAS as biomarker for Panitumumab response in mCRC,PFS HR significantly different depending on K-ras status (P .0001) Percentage decrease in target lesion g
24、reater in patients with wild-type k-RAS receiving panitumumab,Patients with mutant k-RAS,Mean in Wks,Stratified log rank test: P .0001,115/124 (93),Patients with wildtype k-RAS,1.0,0.9,Proportion With PFS,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,2,4,6,8,10,Events/N (%),Median in Wks,Pmab + BSC,BSC alone,
25、114/119 (96),12.3,7.3,19.0,9.3,HR: 0.45 (95% CI: 0.34-0.59),12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,52,Weeks,Proportion With PFS,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48,50,Weeks,Pmab + BSC,BSC alone,Mean in W
26、ks,76/84 (90),Events/N (%),Median in Wks,95/100 (95),7.4,7.3,9.9,10.2,HR: 0.99 (95% CI: 0.73-1.36),52,Amado et al. JCO 2008,NCIC/AGITG 的KRAS分析,初步数据 相似的结果 最终数据即将公布,Van Cutsem ASCO 2008,哪种更加有效?,双靶点治疗?,PACCE Study,First-line Avastin + CT +/- panitumumab,Panitumumab Ox-CT Bevacizumab,Ox-based CT N = 800
27、 Inv choice,Iri-based CT N = 200 Inv choice,Ox-CT Bevacizumab,Panitumumab Iri-CT Bevacizumab,Iri-CT Bevacizumab,R A N D O M I Z E,1:1,1:1,S C R E E N I N G,Hecht et al. World GI Barcelona 2007,Limited Update of PFS Ox-CT Cohort,Pmab+bev/Ox-CT Bev/Ox-CT,HR= 1.29 (95% CI: 1.05-1.58),ITT set,Hecht et a
28、l. World GI Barcelona 2007,Similar Result with Irinotecan, Hecht J ASCO GI 08,Randomised Phase III Punt et al ASCO 2008,Two targeted agents Increased toxicity, skin and diarrhoea,新的靶点 - 1,胰岛素样生长因子 上调 细胞增生, 抑制凋亡, 诱导VEGF 体内试验与奥沙利铂有协同作用 Bauer TW Annals of Surgical Oncology 2008 临床试验正在开展中,新靶点 - 2,肝细胞生长因
29、子 与EGFR的促细胞增生作用有协同作用 原发灶中低表达 2 转移灶中高表达 18 Zeng et al Cancer Letters 2008 临床试验开展单抗和小分子靶向药物的研究,“个体化治疗”,一线化疗 单药或FOLFOX/FOLFIRI 根据肿瘤特性 + VEGFRI or EGFRI in RAS wild type 二线治疗 转到联合化疗 + VEGF 或转到 EGFRI（RAS WT） 三线治疗 EGFRI （既往未采用且RAS WT）,Topo1/TS/ERCC1/MSI,Single agent - Capecitabine,Combination Irino/oxaliplatin,RAS WT/mut,Add Cetuximab?/ Bevacizumab for both?,CT/MRI/USOUND,Bevacizumab,Many Potential subgroups We need more translational studies to generate new questions,IGF1-R,?IGF1-R Ab,C-met,?C-met-I,全世界携手共同提高肿瘤治疗效果 ! MOUs like ours are the way to help achieve this goal Xie xie 谢谢,