腫瘤分子靶向治療-王樹濱

1、Molecular Targeted Therapy of Cancer墜（笏尢歹第二臨床歹陵 探御詢心久保陵腫瘤科王樹濱腫瘤分子靶向治療的發(fā)展Treatment Modalities in Cancer+ INEW AGENTSChemotherapyBrainAntibodiesBoneBiologic TherapyChemotherapy Biologic TherapyNEW rARGGene tlicrapySignal transduction Mortality due Cancer has decreased :-Improved screening-中rly diagnos

2、isChemotherapy-Improved treatment60Lung and BronchusBreastColon and RectumUte rustStomachOvaryPan creasU.2一 B-ndod OOOOOL 唇OJpett:cmco oo oo OJCU6 6 6ellU9ooXoooo666LLL暑 9魚 及ZE 0卜6L 896b 996L 096 L 09? 096. 9雖 9雖 kS6F OIS6L 0S6L 9 寸s 9 寸2 寸莒 0J 0善 養(yǎng)b 9E6L 寸霽 0E6LYear of Death655545352515-Gemtuzuma b

3、Evolution of Chemotherapy呎h”1945 1950 4955 1960 1965 1970 1975 1980 1985 1990 1995 2000YearKinase Inhibition by Competing with ATPBinding DorrunGoldman JM Melo JV. NEnql JMsd. 2001.344:1084-1086.New cancer treatments present a complex picture.HER2RinhibitorsIGF-1RinhibitorsMetastasesInhibitorsrmTOR

4、inhibitorsCell Cycle inhibitorsEGFR inhibitorsHSP90 inhibitorsAurora Kinase inhibitorHIF inhibitorMEK inhibitorsAnti-Angiogenesisl Raf inhibitor/ MUC-1DirectedantibodiesSrcinhibitorFarnesylTransferaseInhibitorsProteasomeinhibitorDeathReceptorsTubulin- interacting agentsKinesinsMdm2 inhibitorHDAC Inh

5、ibitorsPro-apoptotic drugsMedici n e s i n D e v e l o p m e n t f o rCancerTEDACEThere are tew things that cause patie nts more fear and uncertainty as a cancer diagnosis. Yet today because of a steady siream of new a rd improved medicines and treatnnts ancer can increasingly be managed and evei be

6、aten Patients and tlieir faiTiilies are looking for even mere aixl better treatiTients., and AiTiericAs research biopharniaceutical companies are responding.BiophariTiaceLitical researchers are working on 399 medicines tor can匚© hlmny are high-tech weapons that fight the disease in new ways whi

7、le some involve research on new ways to use existing medicines. The research is being conducted by 1 78 phariTiaceiitical and biotechnology companies and by the National Cancer Institute-The medicines in developmentall in either clinical trials or under Food and Drug Administration review include 62

8、 tor lung cancer the leading cause of cancer 日math in the United States; 49 for breastcancerf which is expected to strike n-»re than 2COrOOD American women this year; 35 for colon crmnoeTf thw third most common cancer in both men and women in this country; and 50 torMedicines in Development for

9、 CanchtLokfi* inc«r3BhrfcfcrCinoor BrilnCin«r &cjdCinoQrKktiaZinc-fff Lcukiph UrCincsr LurCinoor Lymph二m】OMrianCinoQi PjrKrodkCinoQr FrodJeCinoor Srccma SklnCincer MKHunx毎 3amxhCmoQr can«rn：iiri ccMiiian; Otar Cimm urvan崗 Uinwfs'Some medicines are listed in more Ihan on«e

10、 colegory. The iirst in a new class of drugs prevents acute and delayed nausea and vomiting associated with chemotherapy.399 Medicines in Development Offer Hope in the War on Cancer腫瘤分子靶向治療的概念EDITORJournal of Clinical OncologyWhat Is Targeted Therapy?George W. Sledge Jr, Indiana University School of

11、 Medicine, Indianapolis, INJOtMjALWClinical Oncology腫瘤分子靶向治療的定義就是針對性地瞄準一個靶位 進行治療“有的放矢的治療"腫瘤靶向治療的三個層次器官靶向：某種藥物或方法只對某個器官的腫瘤有效，如腫瘤 的介入治療、射頻熱療等。細胞靶向：只針對某種類別的腫瘤細胞，藥物或制劑進入體內(nèi) 后可選擇性地與這類細胞特異性地結(jié)合，從而消滅 腫瘤細胞，如網(wǎng)、希羅達、脂質(zhì)體阿霉素等。分子靶向：針對腫瘤細胞特有的受體，關(guān)鍵基因和調(diào)控分子為 靶點的治療（阻斷癌細胞信號傳導(dǎo)通路中某一個分 子靶點），抑制腫瘤細胞生長的方法。IntestineLiverTu

12、mor»normal tissue藥代學(xué)靶向pecitabine-DFCRCyDCapecitabineCapecitabine :Tumor Activating 5-FU ProdrugThymidinephosphorylase (TP)5 -DFCR, 5 -deoxy-5-fluorocytidine; 5 -DFUR, 5 -deoxy-5-fluorouridine; CyD, cytidine deaminase; minimal expression in BM,CE, carboxylesterase: preferentially expressed in li

13、ver, not in Gl tract腫瘤化療是不是分子靶向治療?Synthesis of cellular compon ents needed forDNA synthesisReplication of DNA genomeSynthesis of cellular comp on ents for mitosis3 LOG KILL, 1 LOG REGROWTHLow toxicity 一 useful for breast and prostate cancers.Anticancer effect for lymphoma and myelomaCytotoxic Drugs&

14、gt; For the most part DNA is the target The effect is non-specific Tumours are somewhat more sensitive because They attempt to replicate their DNA more often than n ormal tissues Higher level of proliferation Normal highly proliferative tissues are at risk The difference between efficacy and toxicit

15、y can be smallConventional Anticancer TherapiesHorm onalCorticosteroidsCytotoxic alkylating agentsCytotoxic. anti-metaboliteCytotoxic.topo-inhibitorsCytotoxicanti-mitoticsTraditional Chemotherapy Agents Advantage- Activity in certain malignancies Disadvantages=Selectivity Target rapidly dividing cel

16、ls Minimal efficacy in advanced disease 一 ToxicitiesCytotoxic腫瘤化療是不是分子靶向治療?攻擊靶點的目標(biāo)不同（細胞毒藥物：抑制增值迅速的腫瘤細胞的DNA合成<（殺滅作用）分子靶向藥物：細胞癌變過程中的受體或轉(zhuǎn)導(dǎo)過程 、中關(guān)鍵性酶（改錯作用）藥物開發(fā)程序不同細胞毒藥物：篩選-療效-靶點（分子靶向藥物：靶點-設(shè)計-療效Integration of Surrogate Endpoints in Clinical Drug Development: Addressing The Challenges of Clinical Develo

17、pmentDrug Proof of Target一 Does drug hit target in patientsTargetVBiological ResponseVClinicalSurrogateClinicalEndpoint Proof of Activity/MechanismMeasure biological response in patients Understand molecular mechanism in patie ntsProof of EfficacySurrogate biomarker correlated with approvable clinic

18、al endpoint Approvable Clinical EndpointGenentech腫瘤分子靶向治療的特點Cancer is a multistep processCures need to attack many features of tumorsCreating owninstruct!ons to growAvoidi ng cell deathEndless potential to replicateGrowing new blood supply8Ignoring body's ownorders to stop growingTissue invasion

19、& metastasisAdapted from Hanahan and Weinberg, Cell 2000Targeted Therapies Advantages一 Selectivity Molecular targets一 Toxicities Decreased normal cell destruction Disadvantages-Unknown CombinationsCytostatic Dosing regimens _ Long-term 一 Cost腫瘤分子靶向治療的毒性 Drugs targeting EGFR:一 MoAbs: cetuximab, p

20、anitumumab一 TKIs: gefitinib, erlotinib Drugs targeting HER-2/neu:一 MoAbs: trastuzumab, pertuzumab一 TKIs: lapatinib Drugs targeting an giogenesis:一 MoAbs: bevacizumab一 Other: TRAPS, TKIs Multitarg etede nts:Drugs targeting PI3K-mT0R:- PI3k inhibitors: TKIs一 mTOR inhibitors: S-TKIs (rapa nalogs)Drugs

21、targeting IGFR-2:一 MoAbs一 TKIs一 TKIs: imatinib, sorafenib, sunitinibEGFR抑制劑相關(guān)皮膚毒性皮疹（座瘡樣皮疹）皮膚干燥指甲改變毛發(fā)改變毛細血管擴張和色素沉著Estrogen Receptor: 70-75% of breast cancers are ER+Triple Negative: 10-15% of breast cancers are ER/PR- and HER-2 *In Summary:A Paradigm for Tailored MedicineTraditional Chemotherapy Hist

22、ological profile of the tumor Treatment decisions according to population prognostic and predictive factors Non-selectivity and CytotoxicTargeted Therapy Molecular profile of the tumor Treatment decisions according to individual prog no Stic and predictive factors Selectivity and Non-cytotoxicWBEcaJ

23、 二。Q2&Improvement of treatment quality.Pote ntial Advantages Less toxicity In creased efficacy腫瘤分子靶向治療的分類腫瘤分子靶向治療的分類Clinical Anti-EGF Receptor TherapiesSignal Transductionq Q LigandsMonoclonalan tibodies(Cetuximab, Panitumumab,Matuzumab, h-R3, MDX447)Tyrosine kinase inhibitors(Gefitinib, Erlotin

24、ib, CM033EKB-569, AEE788, GW572016,PKI-166)按結(jié)構(gòu)分類 NCI分類按靶點分類腫瘤分子靶向治療的分類National Cancer InstituteU.S. National Institutes of Health I 1937-1950s、 tk ip animationsMore Than 70 Years ofExcellence in Cancer Research2004年NCI分類Small molecular drugs小分子藥物 Monocolonal antibodies單克隆抗體 Apoptosis-i

25、nducing drugs抗凋亡藥物An gioge nesis抗血管抑制劑 Cancer vacci nes腫瘤疫苗 Gene therapy基因治療Current Targeted Agents Shopping List Signal transduction/Cell-cycle inhibitorsVX680-Vorinostst Decitabine BortezomabFDA appoved for one or more indication Gefitinib is no Ion ger available in the USA exceptunder clinical st

26、udy or when continuing on therapy-Dosatinib Stat-3 inhibitors Gene therapy Wild type P53-Antisense Vaccines-Tumor/dendritic cell-Peptides Viral vaccine Angiogenesis inhibitors Bevacizumab* Interferon-a/b* ZD6474/ZD2171 LY317615-Thrombospondin Receptor-targeted therapy Multitargeted Imatinib mesylate

27、* Sunitinib* Sorafenib* Lapatinib Anti-HER-2 Trastuzumab* Anti-EGFR Erlotinib* Gefitinib Cetuximab*Pan itumumab*Multi-targeted inhibitors 47(17%)Angiogenesis inhibitors44 (16%)Epigenetic modulators16 (6%)Single-target signal transduction inhibitors 32 (12%)DATAMONITOR腫瘤分子靶向治療的分類（推薦）Immunomodulatory

28、or Immunoconjugated therapeutics 57 (21%)Cell cycle andapoptosis targetedagents78 (28%)Source: Datamonitor腫瘤分子靶向治療的實例腫瘤分子靶向治療的實例卜降輅腸大腸癌的分子靶向治療Molecular Targeted Drugs inColorectal CancerFDA : Agents Approved inColon Cancer 2008AdjuvantLevamisol (+ 5FU)1990Leucovorin (+ 5FU)1994 <SxaHplatjp>(FO

29、LFOX)2005:-Capecitabi ne 2005Fir§izlineCFIuorouracil, 5-F1962Leucovorin (+ 5FU)1991<4dnote>(+ 5FU/LV)2000-Capecitabi ne2001Refractory-Irinoteca n1996, 1998 -Oxaliplatin (+ 5FU/LV)2002CetuximabPanitumumab2006-Oxaliplatin (+ 5FU/LV)2004_Bevacizumab2004History of anti-cancer durgs forthe tre

30、atment of MCRC第二次飛躍第一次飛躍Changed 5-FuSchemeBiochemiccil Modulati4nMainstayInfuskn 5-FUBol” 5-FUBest Support Caro60-70's80-90*5第三次飛躍Combinted cytotoxic drugIrinoteconOxaliplatinCapadtabineIntergratedTarget drugBevaeizumabCctuxitnabPanitumumabStop aiig Go1elrvQlo eQorM200M200-4Thorapy for Motastati

31、c Colorectal CancerOn»o</neia for FQM環(huán) f/x> (Tnrocf SUaroxIrlnotoc/i n <U1 - 1 1J-Prxl-mlr>y|l4» «g«» nt2n<f-lieno.*rx>畑«(>«*八Q <»r weft*OovmcI m rrwt> Cot<jximat»i m>«5POO 1199620042004-Today's Issue Molecular Ta

32、rgeted Drugs in Colorectal Cancerevacizumab humanized IgG-1 against VEGF Optimal dose under evaluation FDA approved dose 5mg/kg Half-life: 20d+Cetuximab Chimeric IgG-1 against EGFR 30% murine 3%HSR ADCC? Half-life:5dayPanitumunwb Fully human IgG-2 against EGFR 1%HSR ADCC: NoHalf-life: 7.5dayAnttVeGF

33、tTho VEGF Pathway and anti<VEGF AgantsAnll.VEGF4一肩怡青an<itx>d»<5 滬VEQF%oluW«VEOF(MvacaunAi/receptors/ ocr-TRAP%FabmarAcaEGFR KtrtftonSJ>Vt<XR1 and R2)Agents targeting the VEGF pathwayAnti-VEGF antibodiesVEGF(bevacizumab)Ribozymes I (ang iozyme) *、二Endothelial cellSolubleVE

34、GFreceptors(VEGF-Trap)Anti-VEGFRantibodies(IMC-2C7)Small-moleculeVEGFR inhibitors(PTK/ZK)Bevacizumab : Randomised Trials in Progress Patients with Metastatic Colorectal CancerAdjuvantNSABP C082nd lineE3200+IFL十 FOLFOXBIBB-C+FOLFIRI+FOLFOXAVANTNO16966+XELOXHurwitz et al NEJM2004Phase III Trial of Bev

35、acizumab inMetastatic Colorectal Cancer (AVF2107g)Previously untreatedMCRC(n=923)*5.0 mg/kg q2wIFL + Placebon=4hIFL + Bevacizumab*n 二 4025-FU/LV +Bevacizumab*n=110PD*PrimaryEndpoint:Survival*P.atients, receiving Bevacizumab could continue therapy past disease progress!on in combi nation with sec ond

36、 line therapyIFL; irinotecanluoouracil, leucovorinHurwitz et al NEJM2004Phase III Trial of I FL +/- Bevacizumab inFirst-Line MCRC: Efficacy SummaryIFL + Placebo (n = 412)IFL + Bevacizumab (n=403)P ValueMedian survival (mo)15.620.30.00003PFS (mo)6.210.6<0.00001RR(%)35450.0029Duration of response (

37、mo)014IFL+BEV > IFLPhase III Trial of IFL +/- Bevacizumab inFirst-Line MCRC: Survival Median survival: 15.6 vs 20.3 mo ( P<0.001) Error bars represent 95% confide nee intervals6u->AJns 4ua>ala>dIFL+BEV > IFLBICC-C Period 1 & 2:Treatment Regimensfactorial designAfter A

38、pril 2004:Capelri closedBevacizumab added to FOLFIRI and mIFLPrimary endpoint: TTPFuchs C, et al. ASCO 2006. Abstract 3506;Mitchell E, et al. ASCO 2005. Abstract 3652esNAJns 0OIILcossalEOJa.jo uotoaod.9$7.6343.2詡 o666O.O.6O.O.6_oBICC-C Period 1: PFSData thru Mar 1,2006 (ITT)'FOLFIRI mlFL CapelRI

39、Median PFSHRRegimen(Months)(95% Cl)P ValueFOLFIRI7.6ml FL5.81.550.0009(12,2.0)CapelRJ551.470.0049(11,1-9)1015202530Months Fuchs et sL ASC02006 Ab 3506FOLFIRI > mIFL=CapeIRIOSSm 畫?_BUpdatedResEtsPinnate of SiMijectts Wlio Survived臺7莎8.1FICLn3f?-:a世 w:t1fr*>2RI-家g sa§11Fuchs G ef g ASCO 200

40、T bbsy24027TTREE 1 & 2 研究 150例病人230例病人R ATO ND O MASCO 2005 Ab 3515Efficacy: TREE-1 and TREE-2*per protocol populationHoctister er a/.F ASCO 2006FOLFOXbFOL|CAPEOX-BEV N=49+ BEVN=71-BEV N=50+ BEV N=70BEVM=48+ BEVN=72Conf. RR4353|j 221413548TTF ( mo)4.45.5TTP (mo)8.79.91 10.3OS (

41、mo)19.226.017.920.717.2127 0FOLFOX+BEV > FOLFOX線治療FOLFOX4N=317XELOXN=317RecruitmentFeb 2004 - Feb 2005Recruitme ntJune 2003 一 May 2004NationalComprehensiveNO16966 study designInitial 2-armopen-label study(N=634)XELOX + placebo N=350XELOX + bevacizumab N=350FOLFOX4 + placebo N=351FOLFOX4 + bevaciz

42、umab N=350Protocol amended to 2x2 placebocontrolled design after bevacizumabphase III data1 became available(N=1401)Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) NCCNNationalComprehensive撫九pFS XELOX non-inferiority:primary objective met based on ITTHR = 1.04 97.5% Cl 0.93-1.16Upper limit W 1.2

43、3(non-inferiority margin)15202530MonthsFOLFOX/FOLFOX+placebo/FOLFOX+bevacIzumab XELOX/XELOX+placeboZXELOX+bevacizumabN=1017; 826 events N=1017; 813 eventsXELOX = FOLFOX4I XELOX/FOLFOX4+BevPhase III Trial of FOLFOX +/-Bevacizumab in 2nd Line MCRC（E3200） Secondary end points: ORR, PFS, safetyGiantonio

44、 et al. ASCO 2005*Third arm discontinued after predetermined interim analysis demonstrated the inferiority of bevacizumab compared with FOLFOX4.FOLFOX4; 5-FU, leucovorin, oxaliplatinPhase III Trial of FOLFOX +/- Bevacizumab in 2ndLine MCRC (E3200): PFS and OS DiscrepancyFOLFOX+BEV > FOLFOXToday&#

45、39;s Issue Molecular Targeted Drugs in Colorectal Cancerevacizumab humanized IgG-1 against VEGF Optimal dose under evaluation FDA approved dose 5mg/kg Half-life: 20d+Cetuximab Chimeric IgG-1 against EGFR 30% murine 3%HSR ADCC? Half-life:5dayPanitumunwb Fully human IgG-2 against EGFR 1%HSR ADCC: NoHa

46、lf-life: 7.5dayEGFR KtrtftonAnttVeGFtTho VEGF Pathway and anti<VEGF AgantsAnll.VEGF4一肩怡青an<itx>d»<5 滬VEQF%oluW«VEOF(MvacaunAi/receptors/ ocr-TRAP%FabmarAcaSJ>Vt<XR1 and R2)wnd (EGFjGF-dGfowtfi Effects ProlileratkxK ditferentatkrnAngiogenesis Effects Blood vesselnYaSIvRi H

47、rOwowSnRatfiation or selected chemotherapy agentsmembraneRole of the EGFR inSignal Ttansduction and TVmor ProgressionCell Motility andMetastasis Cd adhesion, in血eness 齊Harari PM Huang 沁Clin Cancer Res &323,2000Cetuximab: Randomised Trials In ProgressPatients with Metastatic Colorectal CancerAdju

48、vantINT0147PETACC-81st line 2nd line3rd lineCRYSTAL BOND+FOLFIRIAfter irinoteca nOPUS EPICBONDNCIC CO.17+FOLFOXAfter oxaliplatinNCIC CO.17: RandomizedPhase III Trial in Refractory mCRCFailed or intolerant to all recommended therapiesEGFRpositive(by IHC)Stratificati on Center ECOG PS (0 or 1 vs. 2)randomizeCetuximab* + BSCBSC alonePD orUnacceptableToxicity° Cetuximab 400 mgZm2 IV week 1 then 250 mg/m2 IV weeklyPrimary end point: Overall survivalSecondary end points: PFS, ORR (RECIST),