mTOR抑制剂在癌症治疗中的应用.ppt

mTOR Inhibitors(mTOR抑制剂抑制剂)in Cancer TherapymTOR 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)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信号通路中的下游分子)mTOR is a central regulator of protein synthesis Activated by mutations in cancerNutrientsGrowth FactorsIGF,EGF,VEGF etcPI3Kglucose,amino acids,etc AKTmTOR(哺乳动物雷帕霉素靶蛋白)mTOR Pathway ActivationProteinSynthesisGrowth Factors Cell Growth&ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1Regulators 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(无限制的癌细胞无限制的癌细胞生长和扩散生长和扩散)mTOR ActivationIncreased synthesis of multiple proteins,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 cellmTOR-Linked Pathway Activation in Selected 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%TGFa a/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-k kBCyclin D1Rapamycin(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 derivatives with improved pharmacokinetic properties Clinical development of mTOR inhibitors as anticancer agentsClinical 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 RapamycinFormulation,and administration:different Temsirolimus:Administered Intravenously Deforolimus:administered Intravenously Everolimus:administered OrallymRCCStandards for RCC Therapy by Phase III Trial after ASCO 2007 SettingPhase IIITreatment-naveGood or intermediate risk*SunitinibBevacizumab+IFN-a aPoor risk*TemsirolimusSunitinibPreviously treatedPrior cytokine SorafenibPrior VEGFr-TKI?Prior mTOR inhibitor*MSKCC risk statusRAD001(everolimus)OOO HOOONOOOOOO HOOH 10 mg/5 mgEverolimus(RAD001)(口服口服mTOR抑制剂抑制剂)Rapamycin derivative Selective inhibitor of mTOR Metabolized by CYP3A4 isozyme,T1/2 30 hours Crosses bloodbrain barrier Biomarker-guided monotherapy dose selection 10 mg/day 70 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(低氧低氧诱导诱导因子因子)/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 therapy Everolimus has both antiangiogenic and antiproliferative activity;response were observed in previously treated mRCC(uncontrolled phase II study)Better Inhibition of p70S6 Kinase With Daily Schedule01234567Tumor050100Time,daysInhibition of p70S6 Kinase Activity,%5020703010510Daily dosing,mgWeekly dosing,mgContinuous target inhibition is predicted to be achievable through the use of daily dosing schedulesTanaka et al.,manuscript in preparation 2007.Phase II Trial of RAD001 in mRCC(Amato)Jac et al.ASCO,2007.Abstract 5107N=37N=39Median=11.17+(2.00 31.53+)MonthsMedian=24.17+MonthsProgression-Free SurvivalOverall SurvivalTime(months)Time(months)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 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 studyRANDOMIZATION2:1Placebo+BSCUpon Disease ProgressionInterim analysisInterim analysisN=410 Stratification Prior 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+BSCPlacebo+BSCEverolimus+BSCPlacebo+BSC(n=138)RAD001+BSC(n=272)透明细胞癌透明细胞癌Treatment given in 28-day cyclesProgression-Free Survival by Treatment Central Radiology Review100806040200024681012Probability,%Hazar