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1、会计学1mTOR抑制剂在癌症治疗抑制剂在癌症治疗(zhlio)中的应中的应用用第一页，共27页。mTOR Mammalian Target of Rapamycin (哺乳哺乳动动物物(brdngw)雷帕霉雷帕霉素靶蛋白素靶蛋白)A central regulator of cell growth and metabolism (控制细胞的生长控制细胞的生长(shngzhng)和代谢和代谢) 第1页/共26页第二页，共27页。mTOR is an intracellular serine-threonine kinase (丝氨丝氨酸酸-苏氨酸激酶苏氨酸激酶(jmi) mTOR is down
2、stream 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 synthesisActivated by mutations in cancerNutrientsGrowth FactorsIGF, EGF, VEGF etcPI3Kglucose, amino acids, etc Mutations Mutations in cancerin cancerAKTS6kS6keif-4eeif-4ePro
3、tein SynthesisProtein SynthesisGrowth &Growth &ProliferationProliferationBioenergeticsBioenergeticsAngiogenesisAngiogenesismTOR(哺乳哺乳动动物物(brdngw)雷帕霉素雷帕霉素靶蛋白靶蛋白)第2页/共26页第三页，共27页。mTOR Pathway ActivationmTOR Pathway ActivationProteinSynthesisGrowth Factors Cell Growth &ProliferationBioenergeticsAngiogen
4、esismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1Regulators 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 c
5、an 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生长(shngzhng)和扩散和扩散)第3页/共26页第四页，共27页。mTOR ActivationmTOR ActivationIncreased synthesis of multiple proteins, including:Hypoxia-Inducible Factors (HIFs, 低氧低氧诱导诱导(yudo)因子因子): expression of angiogenic
6、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页第五页，共27页。mTOR-Linked Pathway Activation in Selected CancersBreastNETColorectalLungRenal Cellp-Akt, 42%PTEN, 15%41%
7、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-k kBCyclin D1第5页/共26页第六页，共27页。Rapamycin (siroli
8、mus)-雷帕霉素雷帕霉素n n Isolated in 1975 on the island of Rapa Nui n nApproved for prevention of kidney transplant rejection in the US and Europe n nFound to have broad anticancer activity against a panel of human cancer cell lines by the U.S. NCI in the 1980s n nRapamycin derivatives with improved pharmac
9、okinetic properties Clinical development of mTOR inhibitors as anticancer agents第6页/共26页第七页，共27页。Clinical Development of mTOR Inhibitors(Derivates of rapamycin )n nTemsirolimus (CCI-779, Torisel, Wyeth Pharmaceuticals) n nEverolimus (RAD001, Afinitor, Novartis)n nDeforolimus (AP23573, ARIAD Pharmace
10、uticals and Merck & Co)mTOR inhibition: Similar MechanismmTOR inhibition: Similar Mechanism of Action of Action 第7页/共26页第八页，共27页。mTOR inhibition (Similar mechanism of action)第8页/共26页第九页，共27页。mTOR Inhibitors: Derivates of RapamycinFormulation, and administration: different n nTemsirolimus: Administer
11、ed Intravenously n nDeforolimus: administered Intravenouslyn nEverolimus: administered Orally第9页/共26页第十页，共27页。mRCC第10页/共26页第十一页，共27页。Standards for RCC Therapy by Phase III Trial after ASCO 2007 SettingPhase IIITreatment- naveGood or intermediate risk*SunitinibBevacizumab + IFN- Poor risk*Temsirolimu
12、sSunitinibPreviously treatedPrior cytokine SorafenibPrior VEGFr-TKI ?Prior mTOR inhibitor*MSKCC risk status第11页/共26页第十二页，共27页。RAD001(everolimus)OOO HOOONOOOOOO HOOH 10 mg/ 5 mgEverolimus (RAD001) (口服口服(kuf)mTOR抑抑制制剂剂)Rapamycin derivativeSelective inhibitor of mTORMetabolized by CYP3A4 isozyme, T1/2
13、30 hoursCrosses bloodbrain barrierBiomarker-guided monotherapy dose selection10 mg/day70 mg/week第12页/共26页第十三页，共27页。 Everolimus (RAD001, Afinitor) in RCCRationaleRationale n nAbout 75% of clear cell carcinomas, the function of the von Hippel Lindau (VHL) gene is lost, causing accumulation of HIF (低氧诱
14、导(yudo)因子)/expression of VEGF and PDGF.n nOther proteins in the PI3K-AKT-mTOR pathway are often deregulated in RCC n nUnmet medical needs for Patients who have failed VEGFt-TKI therapyn nEverolimus has both antiangiogenic and antiproliferative activity; response were observed in previously treated m
15、RCC (uncontrolled phase II study)第13页/共26页第十四页，共27页。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 dai
16、ly dosing schedulesTanaka et al., manuscript in preparation 2007.第14页/共26页第十五页，共27页。Phase II Trial of RAD001 in mRCC Phase II Trial of RAD001 in mRCC (Amato)(Amato)Jac et al. ASCO, 2007. Abstract 5107N=37N=39Median = 11.17+(2.00 31.53+) MonthsMedian = 24.17+ MonthsProgression-Free SurvivalOverall Su
17、rvivalTime (months)Time (months)第15页/共26页第十六页，共27页。Objectives (end Point)Primary: PFSSecondary: Safety; Response; Patients reported outcome; OSRECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) 随机随机III期期试验试验(shyn):比比较较RAD001与安慰与安慰剂剂 (phase III, double-blind, randomized trial of RAD0
18、01+ BSC vs Placebo+BSC)第16页/共26页第十七页，共27页。RECORD-1 Phase III study design(随机随机III期试验期试验(shyn):比较比较RAD001与安慰剂与安慰剂) 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 recommend
19、ed termination of studyRANDOMIZATION2:1Placebo + 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进展(jnzhn)的患者的患者MSKCC risk group: favorable, intermediate, or poor=FinalanalysisEverolimus + BSC(n = 272)(n
20、 = 272)Placebo + BSC(n = 138)(n = 138)Everolimus + BSC(n = 272)(n = 272)Placebo + BSC(n=138)RAD001 + BSC(n=272)透明透明(tumng)细胞癌细胞癌Treatment given in 28-day cycles第17页/共26页第十八页，共27页。Progression-Free Survival by Treatment Central Radiology Review100806040200024681012Probability, %Hazard ratio = 0.30 95%
21、 CI 0.22, 0.40Median PFSEverolimus: 4.0 moPlacebo: 1.9 moLog rank P value 0.001 Everolimus (n = 272) Placebo (n = 138) Months延长延长(ynchng)无进展生存期无进展生存期Motzer RJ, et al. ASCO 2008 and Lancet 2008; 372: 44956第18页/共26页第十九页，共27页。Progression-Free Survival by Treatment Investigator Assessment100806040200Pro
22、bability (%)024681012MonthsHazard ratio = 0.3195% CI 0.23, 0.41Median PFSEverolimus: 4.6 moPlacebo: 1.8 moLog rank P value 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页第二十页，共27页。Subgroup Analysis of Progression-Free Surviv
23、al Subgroup Analysis of Progression-Free Survival Central Radiology ReviewCentral 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页第二十一页，共27页。Treatment-Related Adverse Events*Everolimus%, (n = 269)Placebo%, (n = 135)All G
24、radesGrade 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 0Infections10 32 0Pneumonitis8 30 0Dyspnea8 12 0* 1
25、0% 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页第二十二页，共27页。Conclusionsn nEverolimus prolongs progression-free survival in Everolimus prolongs progression-free survival in RCC patients aft
26、er progression on VEGFr-TKI RCC patients after progression on VEGFr-TKI therapiestherapiesn nEverolimus is the first and only agent with Everolimus is the first and only agent with established clinical benefit for the treatment of established clinical benefit for the treatment of patients with RCC a
27、fter VEGFr-TKI therapypatients with RCC after VEGFr-TKI therapyn nEverolimus should be standard-of-care in this Everolimus should be standard-of-care in this setting setting 第22页/共26页第二十三页，共27页。Standards for RCC Therapy by Phase III Trial after ASCO 2008 SettingPhase IIITreatment- naveGood or interm
28、ediate 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页第二十四页，共27页。Everolimus : Development Overviewn nActive in multiple tumor typesn n RCC an
29、d NET- first indicationsRCC and NET- first indicationsn n Lymphoma and TSC- pivotal trials coming Lymphoma and TSC- pivotal trials comingn ngenerally well-toleratedn nOther Proof of Concept and clinical trialsn n Breast cancer, Lung, Gastric, HCC, CRC Breast cancer, Lung, Gastric, HCC, CRC n nCombination therapy with other chemo/target agents第24页/共26页第二十五页，共27页。Thank You ! 第25页/共26页第二十六页，共27页。内容(nirng)总结会计学。Bevacizumab + IFN-。Crosses bloodbrain barrier。Placebo + BSC(n=138)。RAD001 + BSC(n=272)。Treatment-Related Adverse Events*。Rash (皮 疹)。Thank You。第25页/共26页第二十七页，共27页。
