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1、结肠癌的分子靶向治疗结肠癌的分子靶向治疗哪些靶点？哪些靶点？David Goldstein Conjoint Professor UNSW Prince of Wales Hospital关于靶点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 a)Nuclear receptors(e.g. oestrogen)Survival factors(e.g. IGF1)Cytokines(e.g. ILs,
2、IFNs)Deathfactors(e.g. FasL)Anti-growth factors(e.g. TGF-b b)Hormones(e.g. bombesin)FrizzledDisheveledGSK-3b bAPCTubulinTCFIntegrinsb b-Cateninb b-Catenin:TCFE-CadherinCdC42PI3KRacFakCasCrkSrcFynShcNF1RasRTKGrb2SOSRalMEKMAPKMAPKMEKKPLCPKCMosMKKsJNKsELKMyc:MaxMax:MaxFosJUNAbl7-TMRCdC42RacRhoG-ProlAd
3、CyclPKACREBPKCNF-k kBNHR (e.g. ER)NF-k kBP13KAktAkkaIKBPTEN?Stat 3.5Stat 3.5Stat 3.5Bcl XLCaspase 9Cytochrome CJaksBadBidMitochondriaBim, etc.AbnormalitysensorBcl 2Cell death(Apoptosis)Caspase 8FAPFADDBcl 2BaxARFp53MitochondriaMDM2DNA damagesensorCellproliferation(cell cycle)Changesin geneexpression
4、Cycl E:CDK2p21p27E2FsRbp16Cycl D:CDK4p15SmadsRTKCytokine RFasSurfaceAgTGFb bRHPVE7Decoy RHanahan D and Weinberg RA Cell 2000Hanahan D and Weinberg RA Cell 2000老药新用哪种哪种联联合化合化疗疗方案是有效的方案是有效的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 4ERCC1 and XPD SNPS in PBCs, 与预后相关的表型研究Ruzzo A JC
5、O 2007哪种哪种联联合化合化疗疗方案是有效的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; 26:2690-2698 2008Fig 2. CONSORT diagram值值得关注的研究得关注的研究11个个对CPT-11和和LOHP治治疗效果可
6、能有价效果可能有价值的的预测分子分子6个分子个分子标记物采用免疫物采用免疫组化的方法化的方法进行行评估估: excision repair cross-complementing gene 1 (ERCC1); Topoisomerase-1 (Topo1) p53O-6-methylguanine-DNA-methyltranserase (MGMT)cyclooxygenase 2 (COX2),错配修复基因的免疫配修复基因的免疫组化化评估估 (MLH1/MSH2 有四个基因有四个基因评估其基因的估其基因的单链核苷酸多核苷酸多态性性: Glutathione-S-transferase-P
7、1 (GSTP1) A313GATP-binding-cassette-group-B, gene 1 (ABCB1)x-ray-cross-complementing-group 1 (XRCC1) Q399RERCC2 K751Q.UGT1A1*28基因的基因的多种串多种串连重复的启重复的启动子多子多态性性评估估Braun, M. S. et al. J Clin Oncol; 26:2690-2698 2008Fig 3. 不同治不同治疗策略的策略的总生存以及生存以及TOPO1的表达情况的表达情况combinationsequentialMAX Study AGITG Tebbutt N
8、Sargeant D ASCO 2008MSI is a positive prognostic marker6 randomised trials of 5FU vs No Rx, data pooled, 10-19% dMMRMSI status is a predictive factor for 5FU化化疗疗的靶点的靶点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 TargetsMay receive bevacizu
9、mab pastdisease progressionMay receive bevacizumab pastdisease progressionNo bevacizumab past diseaseprogressionIFL bevacizumab的的III期临床研究期临床研究:IFL:bolus 5-FU 500mg/m2leucovorin 20mg/m2irinotecan 125mg/m2given 4/6 weeksBolus IFL + bevacizumab (n=402)Previously untreatedmetastatic CRC5-FU/LV + bevaciz
10、umab (n=110)Bolus IFL + placebo(n=411)5-FU/LV:bolus 5-FU 500mg/m2 leucovorin 500mg/m2 given 6/8 weeksBevacizumab:5mg/kg every 2 weeksHurwitz H, et al. NEJM 2005生存生存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. BEV
11、ACIZUMAB + FOLFOX 4在既往治在既往治疗过的的结直直肠癌患者中的癌患者中的疗效效Kaplan-Meier estimates of progression-free survival (PFS)Folfox/BevFolfoxBevGiantonio, 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 Onco
12、l; 26:3523-3529 2008TREE Studies Oxali/5FU +/_ BevacizumabFig 2. Kaplan-Meier plots of overall 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.
13、Overall survival (intent-to-treat population ITT)Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 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)1.00.80.60.40.2005101520253035Months
14、Survival estimateNo treatment (n=253)No Avastin post PD (n=531)Avastin post PD (n=642)Post-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-progressionAvastinHR=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
15、和功能性超声检查Median overall survival in first-line metastatic CRCBest supportive care06121824Median 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 + be
16、vacizumabMetastasisProliferation/MaturationSurvival/ApoptosisAngiogenesisMAPKMEKGene transcriptionCell-cycle progressionPI3-KRASRAFSOSGRB2PTENAKTSTATpYpYKKpYEGFR 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.
17、et al. J Clin Oncol; 25:1658-1664 2007Fig 2. Progression-free survival (all randomly assigned analysis set)NCIC CTG CO.17: Randomized Phase III Trial in mCRCEGFR EGFR testing testing by IHCby IHC * * Cetuximab 400 mg/mCetuximab 400 mg/m2 2 IV week 1 then 250 mg/m IV week 1 then 250 mg/m2 2 IV weekly
18、 IV weekly Disease Disease Progression Progression ororUnacceptable Unacceptable ToxicityToxicityR RE EGGI IS ST TE ER RR RA AN ND DOOMMI I Z ZE E1:11:1Cetuximab* + BSCBSC aloneFailed or intolerant to all recommended therapies, Failed or intolerant to all recommended therapies, ECOG 0-2, No Prior EG
19、FR directed therapyECOG 0-2, No Prior EGFR directed therapyPrimary Endpoint: Primary Endpoint: Overall Survival Overall Survival Secondary Endpoints: Secondary Endpoints: Progression Free SurvivalProgression Free SurvivalObjective Response Rate (RECIST criteria)Objective Response Rate (RECIST criter
20、ia)Safety and Quality of Life Safety and Quality of Life NCIC CTG CO.17: Progression Free Survival CETUXIMAB + BSCCETUXIMAB + BSCCENSOREDCENSOREDBSCBSCCENSOREDCENSOREDProportion Progression-FreeProportion Progression-Free0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0MONTHSMONTHS0
21、 03 36 69 912121515 HR 0.68HR 0.68 (95% CI =0.57 0.80) (95% CI =0.57 0.80) Stratified log rankStratified log rank p-value 0.0001 p-value 0.0001Study armStudy armMed PFS Med PFS (months)(months)95% CI95% CICetuximab + BSCCetuximab + BSC1.91.91.8 2.11.8 2.1BSC aloneBSC alone1.81.81.8 1.91.8 1.9Jonker
22、et al , NEJM 2007CETUXIMAB + BSCCENSOREDBSCCENSOREDSUBJECTS AT RISKCET+BSC 2872171367837144000BSC285197854426128210Proportion AliveProportion Alive0.00.10.20.30.40.50.60.70.80.91.0MONTHS0369121518212427NCIC CTG CO.17: Overall Survival HR 0.77HR 0.77 (95% CI =0.64 0.92) (95% CI =0.64 0.92) Stratified
23、 log rankStratified log rank p-value = 0.0046 p-value = 0.0046Study armStudy armMS (months)MS (months)95% CI95% CICetuximab + BSCCetuximab + BSC6.16.15.4 6.75.4 6.7BSC aloneBSC alone4.64.64.2 4.94.2 4.9Jonker et al , NEJM 2007Sobrero, A. F. et al. J Clin Oncol; 26:2311-2319 2008EPIC Study Second Lin
24、ePhase III, Oxaliplatin ProgressionHR 0.97HR 0.692转移性移性结直直肠癌一癌一线治治疗 Phase III Folfiri +/- Cetuximab 在在EGFR（）的（）的结直直肠癌癌N=1217 患者PFS 8.9 vs 8.0 months, HR 0.851 p=0.0471 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%哪些人将采用哪些人将采用 EGFRI治治疗疗?一个新的靶点?EGFR Signaling Cascade
25、 and EGFR Signaling Cascade and K-rasK-rasAktSOSFOS MycP13KFKHRmTORPTENMEK 1/2MAPKBADGSK-3ShcGrb-2RasRafJunp27Cyclin D-1LigandLigandSignalSignalAdaptersAdaptersand Enzymesand EnzymesSignalSignalCascadeCascadeEGFREGFR dimerdimerTranscriptionTranscriptionFactorsFactorsSTATK-ras is a small G protein K-
26、ras is a small G protein Self inactivating from GDP to GTP stateSelf inactivating from GDP to GTP stateSwitched off by intrinsic GTPase activitySwitched off by intrinsic GTPase activityK-ras mutation leads to constitutive activation K-ras mutation leads to constitutive activation mediated through re
27、duced GTPase activitymediated through reduced GTPase activity Inhibitors upstream may be ineffectiveInhibitors upstream may be ineffectiveRandomization stratificationECOG score: 0-1 vs. 2Geographic region: Western EU vs. Central & Eastern EU vs. Rest of World 1:1PanitumumabPD Follow-up6.0 mg/kg Q2W+
28、 BSC BSCPD Follow-up RANDOMIZEOptional Panitumumab Crossover Study Hypothesis: The treatment effect of panitumumab monotherapy is larger in patients with wild-type k-RAS compared to patients with mutant k-RAS KRAS analysis of panitumumab vs BSCVan Cutsem, Peeters et al. JCO. 2007;25:1658-1664.Amado
29、et al. JCO 2008K-RAS as biomarker for Panitumumab response in mCRCPFS HR significantly different depending on K-ras status (P .0001)Percentage decrease in target lesion greater in patients with wild-type k-RAS receiving panitumumabPatients with mutant k-RASMeanin WksStratified log rank test: P .0001
30、115/124 (93)Patients with wildtype k-RAS1.00.9Proportion With PFS0.80.70.60.50.40.30.20.1002 4 6 8 10Events/N (%)Medianin WksPmab + BSCBSC alone114/119 (96)12.37.319.09.3HR: 0.45 (95% CI: 0.34-0.59)12 141618 202224262830 32 3436 38 4042444648 50 52WeeksProportion With PFS1.00.90.80.70.60.50.40.30.20
31、.1002 4 6 8 10 12 141618 202224262830 32 3436 38 4042444648 50WeeksPmab + BSCBSC aloneMeanin Wks76/84 (90)Events/N (%)Medianin Wks95/100 (95)7.47.39.910.2HR: 0.99 (95% CI: 0.73-1.36)52Amado et al. JCO 2008NCIC/AGITG 的的KRAS分析分析初步数据相似的结果最终数据即将公布Van Cutsem ASCO 2008哪种更加有效哪种更加有效?双靶点治疗?PACCE StudyFirst-l
32、ine Avastin + CT +/- panitumumabPanitumumab Ox-CTBevacizumabOx-based CTN = 800Inv choiceIri-based CTN = 200Inv choiceOx-CTBevacizumabPanitumumab Panitumumab IriIri-CT-CTBevacizumabBevacizumabIriIri-CT-CTBevacizumabBevacizumabRANDOMIZE1:11:1SCREENINGHecht et al. World GI Barcelona 2007Limited Update
33、of PFS Ox-CT Cohort# PFS events (%)Median (95%CI), mos206 (50)9.0 (8.5-10.4)172 (42)10.5 (9.7-11.6)Pmab+bev/Ox-CTBev/Ox-CTHR= 1.29 (95% CI: 1.05-1.58)Proportion Progression-Free100%90%80%70%60%50%40%30%20%10%0%ITT setHecht et al. World GI Barcelona 2007Similar Result with Irinotecan, Hecht J ASCO GI
34、 08Randomised Phase III Punt et al ASCO 2008Two targeted agents Increased toxicity, skin and diarrhoea新的靶点新的靶点 - 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 新靶点新靶点 - 2肝细胞生长因子与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 18Zeng et al Cancer Letters 2008临床试验开展单
35、抗和小分子靶向药物的研究“个体化治个体化治疗疗”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/MSISingle agent - CapecitabineCombination Irino/oxaliplatinRAS WT/mutAdd Cetuximab?/Bevacizumab for both?CT/MRI/USOUNDBevacizumabMany Potential subgroupsWe need more translational studies to generate new questionsIGF1-R?IGF1-R AbC-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 goalXie xie 谢谢
