1、mTOR Inhibitors (mTOR抑制 剂 )in Cancer TherapyRuiRong Yuan, MD, PhDOncology, Novartis &VA Medical Center, UMDNJmTOR 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
2、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 cancerNutrients Growth FactorsIGF, EGF, VEGF etcPI3Kglucose, amino acids, etc Mutations in cancerAKTS6k eif-4eProtein SynthesisGrowth &Prol
3、iferation BioenergeticsAngiogenesismTOR(哺乳 动 物雷帕霉素靶蛋白 )mTOR Pathway ActivationProteinSynthesisGrowth FactorsCell Growth &Proliferation BioenergeticsAngiogenesismTORPI3KEGFIGFVEGFAKTRASERABLAMPKRASTSC1TSC2PTENLKB1 Regulators of mTOR activitymTOR activating mTOR deactivating Mutations of PI3K, Akt, Ra
4、s, GFRs, TSC1/2, PTEN.) may result in inappropriate activation of the pathway and loss of control of functions normally regulated by mTOR Activation 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 ActivationIncreased synthesis o
5、f 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 cellmTOR-Linked Pathway A
6、ctivation 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%TGF/TGFb1, 60%100%VHL, 30%50%IGF-1/IGF-IR, 39%-69%p-Akt, 38%PTEN, 31%TSC1/TS
7、C2NF-kB, 33%LymphomaALK p-AktNF-kBCyclin D1Rapamycin (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
8、 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 (AP235
9、73, ARIAD Pharmaceuticals and Merck & Co)mTOR inhibition: Similar Mechanismof Action mTOR inhibition (Similar mechanism of action)mTOR Inhibitors: Derivates of RapamycinFormulation, and administration: different Temsirolimus: Administered Intravenously Deforolimus: administered IntravenouslyEverolimus: administered Orally
