結(jié)腸癌的分子靶向治療-哪些靶點(diǎn)？課件

1、結(jié)腸癌的分子靶向治療哪些靶點(diǎn)？David Goldstein Conjoint Professor UNSW Prince of Wales Hospital關(guān)于靶點(diǎn)背景化療抗血管生成細(xì)胞內(nèi)二級信使新的方向細(xì)胞通路信息給我們提供許多潛在的治療靶點(diǎn)WNTCellsECMGrowth factors (e.g. EGF, amphiregulin TGF-a)Nuclear receptors(e.g. oestrogen)Survival factors(e.g. IGF1)Cytokines(e.g. ILs, IFNs)Deathfactors(e.g. FasL)Anti-growth f

2、actors(e.g. TGF-b)Hormones(e.g. bombesin)FrizzledDisheveledGSK-3bAPCTubulinTCFIntegrinsb-Cateninb-Catenin:TCFE-CadherinCdC42PI3KRacFakCasCrkSrcFynShcNF1RasRTKGrb2SOSRalMEKMAPKMAPKMEKKPLCPKCMosMKKsJNKsELKMyc:MaxMax:MaxFosJUNAbl7-TMRCdC42RacRhoG-ProlAd CyclPKACREBPKCNF-kBNHR (e.g. ER)NF-kBP13KAktAkkaI

3、KBPTEN?Stat 3.5Stat 3.5Stat 3.5Bcl XLCaspase 9Cytochrome CJaksBadBidMitochondriaBim, etc.AbnormalitysensorBcl 2Cell death(Apoptosis)Caspase 8FAPFADDBcl 2BaxARFp53MitochondriaMDM2DNA damagesensorCellproliferation(cell cycle)Changesin geneexpressionCycl E:CDK2p21p27E2FsRbp16Cycl D:CDK4p15SmadsRTKCytok

4、ine RFasSurfaceAgTGFbRHPVE7Decoy RHanahan D and Weinberg RA Cell 2000Hanahan D and Weinberg RA Cell 2000老藥新用哪種聯(lián)合化療方案是有效的FOLFOX 奧沙利鉑ERCC1, TS levels關(guān)于外周血多態(tài)性和腫瘤基因表達(dá)水平的研究166 例連續(xù)患者 Folfox 4ERCC1 and XPD SNPS in PBCs, 與預(yù)后相關(guān)的表型研究Ruzzo A JCO 2007值得關(guān)注的研究11個對CPT-11和LOHP治療效果可能有價值的預(yù)測分子6個分子標(biāo)記物采用免疫組化的方法進(jìn)行評估: exc

5、ision repair cross-complementing gene 1 (ERCC1); Topoisomerase-1 (Topo1) p53O-6-methylguanine-DNA-methyltranserase (MGMT)cyclooxygenase 2 (COX2),錯配修復(fù)基因的免疫組化評估 (MLH1/MSH2 有四個基因評估其基因的單鏈核苷酸多態(tài)性: Glutathione-S-transferase-P1 (GSTP1) A313GATP-binding-cassette-group-B, gene 1 (ABCB1)x-ray-cross-complementi

6、ng-group 1 (XRCC1) Q399RERCC2 K751Q.UGT1A1*28基因的多種串連重復(fù)的啟動子多態(tài)性評估Braun, M. S. et al. J Clin Oncol; 26:2690-2698 2008Fig 3. 不同治療策略的總生存以及TOPO1的表達(dá)情況combinationsequentialMAX Study AGITG Tebbutt N化療的靶點(diǎn)ERCC或者TOPO1的表達(dá)水平可能是預(yù)測化療有效性的靶點(diǎn)尋找能夠預(yù)測需要接受單藥治療或聯(lián)合化療的靶點(diǎn)MSI狀態(tài)臨床指標(biāo)WCC, LDH, sites of metastases Kohne et al New

7、TargetsMay receive bevacizumab pastdisease progressionMay receive bevacizumab pastdisease progressionNo bevacizumab past diseaseprogressionIFL bevacizumab的III期臨床研究:IFL:bolus 5-FU 500mg/m2leucovorin 20mg/m2irinotecan 125mg/m2given 4/6 weeksBolus IFL + bevacizumab (n=402)Previously untreatedmetastatic

8、 CRC5-FU/LV + bevacizumab (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 2005Kabbinavar, F. F. et al. J Clin Oncol; 23:3706-3712 2005Fig 2. SurvivalGiantonio, B. J. et al. J Clin Oncol; 25:1539-15

9、44 2007Fig 2. BEVACIZUMAB + FOLFOX 4在既往治療過的結(jié)直腸癌患者中的療效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

10、 Oncol; 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 2008Fi

11、g 4. 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)1.00.80.60.40.2005101520253035M

12、onthsSurvival estimateNo treatment (n=253)No Avastin post PD (n=531)Avastin post PD (n=642)Post-progression therapy:12.619.931.8BRiTE registry study: 腫瘤進(jìn)展后再次使用貝伐單抗的生存獲益Post-progressionAvastinHR=0.48 (0.410.57)p0.001Grothey, et al. ASCO 2007VEGF一個有價值的靶點(diǎn)與化療藥物聯(lián)合應(yīng)用哪些患者適合采用？無預(yù)測價值的分子標(biāo)記物可溶性VEGFR水平單藥治療影像學(xué) M

13、RI/CT和功能性超聲檢查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

14、 + bevacizumabMetastasisProliferation/MaturationSurvival/ApoptosisAngiogenesisMAPKMEKGene transcriptionCell-cycle progressionPI3-KRASRAFSOSGRB2PTENAKTSTATpYpYKKpYEGFR Signal TransductionMG1SG2Baselga J EGFR Blockade3rd Line2nd Line1st LineVan Cutsem E J Clin Oncol 2007Panitumumab在結(jié)腸癌中的三線治療Van Cutsem

15、, 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 III Trial in mCRCEGFR testing by IHC * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly Disease Progression orUnacceptable ToxicityREGISTERRANDOMI ZE

16、1:1Cetuximab* + BSCBSC aloneFailed or intolerant to all recommended therapies, ECOG 0-2, No Prior EGFR directed therapyPrimary Endpoint: Overall Survival Secondary Endpoints: Progression Free SurvivalObjective Response Rate (RECIST criteria)Safety and Quality of Life NCIC CTG CO.17: Progression Free

17、 Survival CETUXIMAB + BSCCENSOREDBSCCENSOREDProportion Progression-Free0.00.10.20.30.40.50.60.70.80.91.0MONTHS03691215 HR 0.68 (95% CI =0.57 0.80) Stratified log rank p-value 0.0001Study armMed PFS (months)95% CICetuximab + BSC1.91.8 2.1BSC alone1.81.8 1.9Jonker et al , NEJM 2007CETUXIMAB + BSCCENSO

18、REDBSCCENSOREDSUBJECTS AT RISKCET+BSC2872171367837144000BSC285197854426128210Proportion Alive0.00.10.20.30.40.50.60.70.80.91.0MONTHS0369121518212427NCIC CTG CO.17: Overall Survival HR 0.77 (95% CI =0.64 0.92) Stratified log rank p-value = 0.0046Study armMS (months)95% CICetuximab + BSC6.15.4 6.7BSC

19、alone4.64.2 4.9Jonker et al , NEJM 2007Sobrero, A. F. et al. J Clin Oncol; 26:2311-2319 2008EPIC Study Second LinePhase III, Oxaliplatin ProgressionHR 0.97HR 0.692轉(zhuǎn)移性結(jié)直腸癌一線治療 Phase III Folfiri +/- Cetuximab 在EGFR（）的結(jié)直腸癌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 3

20、8.7%根治性手術(shù)的增加 2.5 to 6% OR 3.0肝轉(zhuǎn)移灶完全消失 9.8 vs 4.5%哪些人將采用 EGFRI治療?一個新的靶點(diǎn)?EGFR Signaling Cascade and K-rasAktSOSFOS MycP13KFKHRmTORPTENMEK 1/2MAPKBADGSK-3ShcGrb-2RasRafJunp27Cyclin D-1LigandSignalAdaptersand EnzymesSignalCascadeEGFR dimerTranscriptionFactorsSTATK-ras is a small G protein Self inactivat

21、ing from GDP to GTP stateSwitched off by intrinsic GTPase activityK-ras mutation leads to constitutive activation mediated through reduced GTPase activity Inhibitors upstream may be ineffectiveRandomization stratificationECOG score: 0-1 vs. 2Geographic region: Western EU vs. Central & Eastern EU vs.

22、 Rest of World 1:1PanitumumabPD Follow-up6.0 mg/kg Q2W+ BSCBSCPD Follow-upRANDOMIZEOptional 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

23、 Cutsem, Peeters et al. JCO. 2007;25:1658-1664.Amado 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 mu

24、tant k-RASMeanin WksStratified log rank test: P .0001115/124 (93)Patients with wildtype k-RAS1.00.9Proportion With PFS0.80.70.60.50.40.30.20.100246810Events/N (%)Medianin WksPmab + BSCBSC alone114/119 (96)12.37.319.09.3HR: 0.45 (95% CI: 0.34-0.59)121416182022242628303234363840424446485052WeeksPropor

25、tion With PFS1.00.90.80.70.60.50.40.30.20.1002468101214161820222426283032343638404244464850WeeksPmab + 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KRAS分析初步數(shù)據(jù)相似的結(jié)果最終數(shù)據(jù)即將公布Van Cutsem ASCO 2008哪種更加有效?雙靶點(diǎn)治

26、療?PACCE StudyFirst-line Avastin + CT +/- panitumumabPanitumumab Ox-CTBevacizumabOx-based CTN = 800Inv choiceIri-based CTN = 200Inv choiceOx-CTBevacizumabPanitumumab Iri-CTBevacizumabIri-CTBevacizumabRANDOMIZE1:11:1SCREENINGHecht et al. World GI Barcelona 2007Limited Update 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%8