mTOR抑制剂在癌症治疗中的应用

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) 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 re

2、gulator 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 &ProliferationBioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC

3、1TSC2PTENLKB1Regulators 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 an

4、d 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

5、 (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%6

6、0%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 a

7、nd 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 ra

8、pamycin ) 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 RapamycinFor

9、mulation, 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

10、-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, T

11、1/2 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 (低氧诱导因子)/expression of VEGF

12、 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)Bet

13、ter 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 prepara

14、tion 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 o

15、utcome; 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 i

16、nterim 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

17、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, %Hazard ratio

18、 = 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 = 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: 44956Progression-Free Survival by Treatment Investigator Assessment100806040200Probability (%)0246

19、81012MonthsHazard 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: 44956Subgroup Analysis of Progression-Free Survival Central Radiology Review1. Motze

20、r et al. J Clin Oncol. 2004;22:454-463.HRNCentral Review0.30410Investigator Review0.31410MSKCC RiskFavorable0.35118Intermediate0.25231Poor0.3961Prior TxSorafenib Only0.29119Sunitinib Only0.30184Both0.28107Age 65 yrs0.32259 65 yrs0.29151SexMale0.29317Female0.3693RegionU.S. & Canada0.24130Europe0.

21、37251Japan & Australia0.102900.41.01.4Hazard RatioEverolimus benefitPlacebo benefit1.20.80.60.21Motzer RJ, et al. ASCO 2008 and Lancet 2008; 372: 44956Treatment-Related Adverse Events*Everolimus%, (n = 269)Placebo%, (n = 135)All GradesGrade 3All GradesGrade 3Stomatitis (口腔炎口腔炎) 40 38 0Asthenia /

22、 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* 10% of everolimus patients and additional selected AEs.Significant

23、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 only agent with established clinical benefit for the treatment of patie

24、nts with RCC after VEGFr-TKI therapy Everolimus should be standard-of-care in this setting Standards for RCC Therapy by Phase III Trial after ASCO 2008 SettingPhase IIITreatment- naveGood or intermediate risk*SunitinibBevacizumab + IFN-a aPoor risk*TemsirolimusSunitinibPreviously treatedPrior cytoki

25、ne SorafenibPrior VEGFr-TKI EverolimusPrior mTOR inhibitor*MSKCC risk statusMotzer RJ, et al. ASCO 2008Everolimus : Development Overview Active in multiple tumor types RCC and NET- first indications Lymphoma and TSC- pivotal trials coming generally well-tolerated Other Proof of Concept and clinical

26、trials Breast cancer, Lung, Gastric, HCC, CRC Combination therapy with other chemo/target agentsThank You ! 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 ag

27、ainst 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 agentsRAD001(everolimus)OOO HOOONOOOOOO HOOH 10 mg/ 5 mgEverolimus (RAD001) (口服口服mTOR抑制剂抑制剂) Rapamycin derivative

28、 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/weekBetter Inhibition of p70S6 Kinase With Daily Schedule01234567Tumor050100Time, daysInhibition of p70S6 Kinase Activity, % 5020703010510D

29、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.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