mTOR抑制剂在癌症治疗中的应用.ppt

mTOR Inhibitors(mTOR抑制剂)in Cancer Therapy,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),mTOR is an intracellular serine-threonine kinase(丝氨酸-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 regulator of protein synthesisActivated by mutations in cancer,Nutrients,Growth Factors,IGF,EGF,VEGF etc,PI3K,glucose,amino acids,etc,Mutations in cancer,AKT,S6k,eif-4e,mTOR(哺乳动物雷帕霉素靶蛋白),mTOR Pathway Activation,ProteinSynthesis,Growth Factors,Cell Growth&Proliferation,Bioenergetics,Angiogenesis,mTOR,PI3K,EGF,IGF,VEGF,ER,ABL,AMPK,TSC1,TSC2,PTEN,LKB1,Regulators of mTOR activity mTOR activating mTOR deactivatingMutations of PI3K,Akt,Ras,GFRs,TSC1/2,PTEN.)may 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(无限制的癌细胞生长和扩散),mTOR Activation,Increased synthesis of multiple proteins,including:Hypoxia-Inducible Factors(HIFs,低氧诱导因子):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,mTOR-Linked Pathway Activation in Selected Cancers,Breast,NET,Colorectal,Lung,Renal Cell,p-Akt,42%PTEN,15%41%HER2,30%36%PI3-K,18%26%,TSC1/TSC2IGF-1/IGF-1RVHL,Ras,50%p-Akt,46%PTEN,35%PI3-K,20%32%EGFR,70%,EGFR,32%60%p-Akt,23%50%Ras,30%PTEN,24%,TGFa/TGFb1,60%100%VHL,30%50%IGF-1/IGF-IR,39%-69%p-Akt,38%PTEN,31%TSC1/TSC2NF-kB,33%,Lymphoma,ALK p-AktNF-kBCyclin D1,Rapamycin(sirolimus)-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 derivatives with improved pharmacokinetic properties Clinical development of mTOR inhibitors as anticancer agents,Clinical Development of mTOR Inhibitors(Derivates of rapamycin),Temsirolimus(CCI-779,Torisel,Wyeth Pharmaceuticals)Everolimus(RAD001,Afinitor,Novartis)Deforolimus(AP23573,ARIAD Pharmaceuticals and Merck&Co)mTOR inhibition:Similar Mechanism of Action,mTOR inhibition(Similar mechanism of action),mTOR Inhibitors:Derivates of Rapamycin,Formulation,and administration:different Temsirolimus:Administered Intravenously Deforolimus:administered IntravenouslyEverolimus:administered Orally,mRCC,Standards for RCC Therapy by Phase III Trial after ASCO 2007,*MSKCC risk status,RAD001(everolimus),10 mg/5 mg,Everolimus(RAD001)(口服mTOR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,Everolimus(RAD001,Afinitor)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 VEGFt-TKI therapyEverolimus has both antiangiogenic and antiproliferative activity;response were observed in previously treated mRCC(uncontrolled phase II study),Better Inhibition of p70S6 Kinase With Daily Schedule,0,1,2,3,4,5,6,7,Tumor,0,50,100,Time,days,Inhibition of p70S6 Kinase Activity,%,Continuous target inhibition is predicted to be achievable through the use of daily dosing schedules,Tanaka et al.,manuscript in preparation 2007.,Phase II Trial of RAD001 in mRCC(Amato),Jac et al.ASCO,2007.Abstract 5107,N=37,N=39,Median=11.17+(2.00 31.53+)Months,Median=24.17+Months,Progression-Free Survival,Overall Survival,Time(months),Time(months),Objectives(end Point)Primary:PFSSecondary:Safety;Response;Patients reported outcome;OS,RECORD-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 trial of RAD001+BSC vs Placebo+BSC),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 study,RANDOMIZATION2:1,Placebo+BSC(n=138),Upon Disease Progression,Interim analysis,Interim analysis,N=410 StratificationPrior VEGFRTKI:1 or 2舒尼替尼或索拉非尼治疗后进展的患者MSKCC risk group:favorable,intermediate,or poor,=,Finalanalysis,Everolimus+BSC(n=272),Placebo+BSC(n=138),Everolimus+BSC(n=272),Placebo+BSC(n=138),RAD001+BSC(n=272),透明细胞癌,Treatment given in 28-day cycles,Progression-Free Survival by Treatment Central Radiology Review,延长无进展生存期,Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956,Progression-Free Survival by Treatment Investigator Assessment,Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956,Subgroup Analysis of Progression-Free Survival Central Radiology Review,1.Motzer et al.J Clin Oncol.2004;22:454-463.,1,Motzer RJ,et al.ASCO 2008 and Lancet 2008;372:44956,Treatment-Related Adverse Events*,*10%of everolimus patients and additional selected AEs.Significant difference between sum of grade 3/4 events for everolimus and placebo groups(P.05).,Conclusions,Everolimus prolongs progression-free survival in RCC patients after progression on 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,Standards for RCC Therapy by Phase III Trial after ASCO 2008,*MSKCC risk status,Motzer RJ,et al.ASCO 2008,Everolimus:Development Overview,Active 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,