mtor抑制剂在癌症治疗中的应用.ppt

mTOR Inhibitors (mTOR 抑制剂 ) in Cancer Therapy RuiRong Yuan, MD, PhD Oncology, Novartis VA Medical Center, UMDNJ 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 ) ? mTOR is an intracellular serine-threonine kinase ( 丝氨 酸 - 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 cancer Nutrients Growth Factors IGF, EGF, VEGF etc PI3K glucose, amino acids, etc Mutations in cancer AKT S6k eif-4e Protein Synthesis Growth Proliferation Bioenergetics Angiogenesis mTOR ( 哺乳动物雷帕霉素靶蛋白 ) mTOR Pathway Activation Protein Synthesis Growth Factors Cell Growth Proliferation Bioenergetics Angiogenesis mTOR PI3K EGF IGF VEGF AKT RAS ER ABL AMPK RAS TSC1 TSC2 PTEN LKB1 ? Regulators of mTOR activity mTOR activating mTOR deactivating ? Mutations 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 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 Activation ↑Increased synthesis of 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 cell mTOR-Linked Pathway Activation in Selected Cancers Breast NET Colorectal Lung Renal Cell p-Akt, 42% PTEN, 15% – 41% HER2, 30% – 36% PI3-K, 18% – 26% TSC1/TSC2 IGF-1/IGF-1R VHL Ras, 50% p-Akt, 46% PTEN, 35% PI3-K, 20% – 32% EGFR, 70% EGFR, 32% – 60% p-Akt, 23% – 50% Ras, 30% PTEN, 24% TGF a /TGF b 1, 60% – 100% VHL, 30% – 50% IGF-1/IGF-IR, 39%-69% p-Akt, 38% PTEN, 31% TSC1/TSC2 NF- k B, 33% Lymphoma ALK p-Akt NF- k B Cyclin D1