mTOR抑制剂在癌症治疗中的应用ppt课件

1、mTOR Inhibitors (mTOR抑制抑制剂剂)in Cancer TherapyRuiRong Yuan, MD, PhDOncology, Novartis &VA Medical Center, UMDNJmTOR Mammalian Target of Rapamycin (哺乳哺乳动动物雷帕霉素靶蛋白物雷帕霉素靶蛋白)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 (丝氨酸-

2、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 synthesis Activated by mutations in cancerNutrientsGrowth FactorsIGF, EGF, VEGF etcPI3Kglucose, amino acids, etc AKTmTOR(哺乳哺乳动动物雷帕霉素靶蛋白物雷帕霉素靶蛋白)mTOR Pathway Activat

3、ionProteinSynthesisGrowth 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 pa

4、thway 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分散)mTOR ActivationIncreased synthesis of multiple proteins, including:Hypoxia-Inducible Factors (HIFs, 低氧诱导低氧诱导因子因子):

5、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

6、, 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/TGFb1, 60%100%VHL, 30%50%IGF-1/IGF-IR, 39%-69%p-Akt, 38%PTEN, 31%TSC1/TSC2NF-kB, 33%LymphomaALK p-AktNF-kBCyclin D1Rapamycin (sirolimus)-雷帕霉素雷帕霉素 I

7、solated 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 Clinica

8、l 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

9、 Mechanism of Action mTOR inhibition (Similar mechanism of action)mTOR Inhibitors: Derivates of RapamycinFormulation, and administration: different Temsirolimus: Administered Intravenously Deforolimus: administered IntravenouslyEverolimus: administered OrallymRCCStandards for RCC Therapy by Phase II

10、I 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 statusRAD001(everolimus)OOO HOOONOOOOOO HOOH 10 mg/ 5 mgEverolimus (R

11、AD001) (口服口服mTOR抑制抑制剂剂) 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 func

12、tion of the von Hippel Lindau (VHL) gene is lost, causing accumulation of HIF (低氧诱导因子低氧诱导因子)/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 therapy Everolimus has both antiangiogenic and

13、 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 inhibit

14、ion 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 Survi

15、valTime (months)Time (months)Objectives (end Point)Primary: PFSSecondary: Safety; Response; Patients reported outcome; OSRECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) 随机随机III期期实验实验:比比较较RAD001与与抚抚慰慰剂剂 (phase III, double-blind, randomized trial of RAD001+ BSC vs Placebo+BSC)RECOR

16、D-1 Phase III study design(随机随机III期实验期实验:比较比较RAD001与抚慰剂与抚慰剂) 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 + BSC(

17、n = )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)Placebo + BSC(n = )Everolimus + BSC(n = 272)Placebo + BSC(n=)RAD001 + BSC(

18、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, %Hazard ratio = 0.30 95% CI 0.22, 0.40Median PFSEverolimus: 4.0 moPlacebo: 1.9 moLog rank P value 0.001 Everolimus (n = 272) Placebo (n = ) Months延伸无进展生存期延

19、伸无进展生存期Motzer RJ, et al. ASCO 2021 and Lancet 2021; 372: 44956Progression-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 0.001 Everolimus (n = 272) Placebo (n

20、= ) Probability, %Motzer RJ, et al. ASCO 2021 and Lancet 2021; 372: 44956Subgroup Analysis of Progression-Free Survival Central Radiology Review1. Motzer et al. J Clin Oncol. 2004;22:454-463.HRNCentral Review0.30410Investigator Review0.31410MSKCC RiskFavorable0.35118Intermediate0.25231Poor0.3961Prio

21、r TxSorafenib Only0.29119Sunitinib Only0.30184Both0.28107Age 65 yrs0.32259 65 yrs0.29151SexMale0.29317Female0.3693RegionU.S. & Canada0.24130Europe0.37251Japan & Australia0.102900.41.01.4Hazard RatioEverolimus benefitPlacebo benefit1.20.80.60.21Motzer RJ, et al. ASCO 2021 and Lancet 2021; 372

22、: 44956Treatment-Related 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

23、0Cough12 04 0Edema peripheral10 03 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) .Conclusions Everolimus prolongs progression-free survival in RCC patients after progression on VEGFr-TKI therapies Everolimus is the first and o