mTOR抑制剂在癌症治疗中的应用.pptx

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1、mTOR Mammalian Target of Rapamycin(哺乳动物雷帕霉素靶蛋白)A central regulator of cell growth and metabolism(控制细胞的生长和代谢控制细胞的生长和代谢)第1页/共26页mTOR is an intracellular serine-threonine kinase(丝氨丝氨酸酸-苏氨酸激酶苏氨酸激酶)mTOR is downstream of growth factor/nutrient and PI3k/AKT signalling pathway(信号通路中的下游分子)mTOR is a central r

2、egulator of protein synthesisActivated by mutations in cancerNutrientsGrowth FactorsIGF,EGF,VEGF etcPI3Kglucose,amino acids,etc Mutations Mutations in cancerin cancerAKTS6kS6keif-4eeif-4eProtein SynthesisProtein SynthesisGrowth&Growth&ProliferationProliferationBioenergeticsBioenergeticsAngiogenesisA

3、ngiogenesismTOR(哺乳动物雷帕霉素靶蛋白)第2页/共26页mTOR Pathway ActivationProteinSynthesisGrowth Factors Cell Growth&ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1Regulators of mTOR activity mTOR activating mTOR deactivatingMutations of PI3K,Akt,Ras,GFRs,TSC1/2,PTEN.)may

4、 result in inappropriate activation of the pathway and loss of control of functions normally regulated by mTORActivation of mTOR can result in loss of cell growth control and enhanced cell metabolism in cancer cells(无限制的癌细胞无限制的癌细胞生长和扩散生长和扩散)第3页/共26页mTOR ActivationIncreased synthesis of multiple prot

5、eins,including:Hypoxia-Inducible Factors(HIFs,低氧低氧诱导诱导因子因子):expression of angiogenic growth factors(eg,VEGF/PDGF)(RCC)Cyclin D1:promotes progression through the cell cycle(MCL)Proteins necessary to transport nutrients(amino acids and glucose)into the cell第4页/共26页mTOR-Linked Pathway Activation in Sel

6、ected CancersBreastNETColorectalLungRenal Cellp-Akt,42%PTEN,15%41%HER2,30%36%PI3-K,18%26%TSC1/TSC2IGF-1/IGF-1RVHLRas,50%p-Akt,46%PTEN,35%PI3-K,20%32%EGFR,70%EGFR,32%60%p-Akt,23%50%Ras,30%PTEN,24%TGF/TGFb b1,60%100%VHL,30%50%IGF-1/IGF-IR,39%-69%p-Akt,38%PTEN,31%TSC1/TSC2NF-k kB,33%LymphomaALK p-AktNF

7、-k kBCyclin D1第5页/共26页Rapamycin(sirolimus)-雷帕霉素雷帕霉素 Isolated in 1975 on the island of Rapa Nui Approved for prevention of kidney transplant rejection in the US and Europe Found to have broad anticancer activity against a panel of human cancer cell lines by the U.S.NCI in the 1980s Rapamycin derivati

8、ves with improved pharmacokinetic properties Clinical development of mTOR inhibitors as anticancer agents第6页/共26页Clinical Development of mTOR Inhibitors(Derivates of rapamycin)Temsirolimus(CCI-779,Torisel,Wyeth Pharmaceuticals)Everolimus(RAD001,Afinitor,Novartis)Deforolimus(AP23573,ARIAD Pharmaceuti

9、cals and Merck&Co)mTOR inhibition:Similar Mechanism of Action 第7页/共26页mTOR inhibition (Similar mechanism of action)第8页/共26页mTOR Inhibitors:Derivates of RapamycinFormulation,and administration:different Temsirolimus:Administered Intravenously Deforolimus:administered IntravenouslyEverolimus:administe

10、red Orally第9页/共26页mRCC第10页/共26页Standards for RCC Therapy by Phase III Trial after ASCO 2007 SettingPhase IIITreatment-naveGood or intermediate risk*SunitinibBevacizumab+IFN-Poor risk*TemsirolimusSunitinibPreviously treatedPrior cytokine SorafenibPrior VEGFr-TKI?Prior mTOR inhibitor*MSKCC risk status

11、第11页/共26页RAD001(everolimus)OOO HOOONOOOOOO HOOH 10 mg/5 mgEverolimus(RAD001)(口服口服mTOR抑制剂抑制剂)Rapamycin derivativeSelective inhibitor of mTORMetabolized by CYP3A4 isozyme,T1/2 30 hoursCrosses bloodbrain barrierBiomarker-guided monotherapy dose selection10 mg/day70 mg/week第12页/共26页 Everolimus(RAD001,Af

12、initor)in RCCRationale About 75%of clear cell carcinomas,the function of the von Hippel Lindau(VHL)gene is lost,causing accumulation of HIF(低氧诱导因子)/expression of VEGF and PDGF.Other proteins in the PI3K-AKT-mTOR pathway are often deregulated in RCC Unmet medical needs for Patients who have failed VE

13、GFt-TKI therapyEverolimus has both antiangiogenic and antiproliferative activity;response were observed in previously treated mRCC(uncontrolled phase II study)第13页/共26页Better Inhibition of p70S6 Kinase With Daily Schedule01234567Tumor050100Time,daysInhibition of p70S6 Kinase Activity,%5020703010510D

14、aily dosing,mgWeekly dosing,mgContinuous target inhibition is predicted to be achievable through the use of daily dosing schedulesTanaka et al.,manuscript in preparation 2007.第14页/共26页Phase II Trial of RAD001 in mRCC(Amato)Jac et al.ASCO,2007.Abstract 5107N=37N=39Median=11.17+(2.00 31.53+)MonthsMedi

15、an=24.17+MonthsProgression-Free SurvivalOverall SurvivalTime(months)Time(months)第15页/共26页Objectives(end Point)Primary:PFSSecondary:Safety;Response;Patients reported outcome;OSRECORD-1(REnal Cell cancer treatment with Oral RAD001 given Daily)随机III期试验:比较RAD001与安慰剂(phase III,double-blind,randomized tri

16、al of RAD001+BSC vs Placebo+BSC)第16页/共26页RECORD-1 Phase III study design(随机III期试验:比较RAD001与安慰剂)410 patients randomized between September 2006 and October 2007 Second interim analysis cut-off:October 15,2007,based on 191 PFS events Independent Data Monitoring Committee recommended termination of stud

17、yRANDOMIZATION2:1Placebo+BSC(n=138)(n=138)Upon Disease ProgressionInterim analysisInterim analysisN=410 StratificationPrior VEGFRTKI:1 or 2舒尼替尼舒尼替尼或索拉非尼治疗后或索拉非尼治疗后进展的患者进展的患者MSKCC risk group:favorable,intermediate,or poor=FinalanalysisEverolimus+BSC(n=272)(n=272)Placebo+BSC(n=138)(n=138)Everolimus+BS

18、C(n=272)(n=272)Placebo+BSC(n=138)RAD001+BSC(n=272)透明细胞癌透明细胞癌Treatment given in 28-day cycles第17页/共26页Progression-Free Survival by Treatment Central Radiology Review100806040200024681012Probability,%Hazard ratio=0.30 95%CI 0.22,0.40Median PFSEverolimus:4.0 moPlacebo:1.9 moLog rank P value 0.001 Evero

19、limus(n=272)Placebo(n=138)Months延长无进展生存期延长无进展生存期Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956第18页/共26页Progression-Free Survival by Treatment Investigator Assessment100806040200Probability(%)024681012MonthsHazard ratio=0.3195%CI 0.23,0.41Median PFSEverolimus:4.6 moPlacebo:1.8 moLog rank P value

20、 0.001 Everolimus(n=272)Placebo(n=138)Probability,%Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956第19页/共26页Subgroup Analysis of Progression-Free Survival Central Radiology Review1.Motzer et al.J Clin Oncol.2004;22:454-463.1Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956第20页/共26页Treatment-Rel

21、ated Adverse Events*Everolimus%,(n=269)Placebo%,(n=135)All GradesGrade 3All GradesGrade 3Stomatitis(口腔炎口腔炎)40 38 0Asthenia/fatigue(疲劳疲劳)37 324 1Rash(皮皮 疹疹)25 14 0Diarrhea(腹泻腹泻)17 13 0Anorexia(厌食厌食)16 16 0Nausea(恶心恶心)15 08 0Mucosal inflammation14 12 0Vomiting 12 04 0Cough12 04 0Edema peripheral10 03

22、0Infections10 32 0Pneumonitis8 30 0Dyspnea8 12 0*10%of everolimus patients and additional selected AEs.Significant difference between sum of grade 3/4 events for everolimus and placebo groups(P .05).第21页/共26页ConclusionsEverolimus prolongs progression-free survival in RCC patients after progression o

23、n VEGFr-TKI therapiesEverolimus is the first and only agent with established clinical benefit for the treatment of patients with RCC after VEGFr-TKI therapyEverolimus should be standard-of-care in this setting 第22页/共26页Standards for RCC Therapy by Phase III Trial after ASCO 2008 SettingPhase IIITrea

24、tment-naveGood or intermediate risk*SunitinibBevacizumab+IFN-Poor risk*TemsirolimusSunitinibPreviously treatedPrior cytokine SorafenibPrior VEGFr-TKI EverolimusPrior mTOR inhibitor*MSKCC risk statusMotzer RJ,et al.ASCO 2008第23页/共26页Everolimus:Development OverviewActive in multiple tumor types RCC and NET-first indications Lymphoma and TSC-pivotal trials cominggenerally well-toleratedOther Proof of Concept and clinical trials Breast cancer,Lung,Gastric,HCC,CRC Combination therapy with other chemo/target agents第24页/共26页Thank You!第25页/共26页感谢您的观看！第26页/共26页