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The model shown was developed with a combination of preclinical and clinical data. The slide shows that daily dosing with either 5 mg or 10 mg is better at maintaining inhibition of pS6K compared with the weekly schedule. 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
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