课件：肝癌靶向治疗新进展June讲诉.ppt

THANK YOU SUCCESS * * 可编辑 * * 慢性肝硬化病是HCC的主要风险因子，对大多数患者来说，HCC是慢性肝硬化病的晚期并发症，导致HCC发生的最显著的风险因子包括慢性丙型肝炎感染、慢性乙型肝炎感染和酒精性肝硬化 在欧洲、北美和日本，导致HCC发生的主要风险因子是丙型肝炎感染和过度饮酒 ，而在经济欠发达国家和亚洲部分地区，导致HCC发生的主要风险因子则是乙型肝炎感染。 其它与HCC发生有关的不太常见的致病因素包括非酒精性脂肪性肝炎、自身免疫性肝炎、原发性胆汁性肝硬化、接触环境中的致癌物及患有新陈代谢疾病 。 * HCC的治疗现状如下： 手术切除、肝移植、局部消融等治愈性外科治疗手段仍然是早期肝癌的首选。约30－40％的早期HCC患者可从中获益。 对于约70％的中晚期无法接受外科治疗的HCC患者，现有放化疗方案均不敏感，TACE是有限的选择之一。 * BMS-582664(brivanib alaninate):VEGFR2, FGFR, Small-molecule tyrosine kinase receptor inhibitor 西地尼布(Cederanib, Recentin,AZD2171), AZ, VEGFR1-3 inhibitor TSU-68(SU-6668) :blocks VEGFR-2, PDGFR, and FGFR * * * Multiple triggers of angiogenesis include local tumor conditions, such as hypoxia, and the binding of both paracrine and autocrine growth factors. VEGF synthesis is turned on by a transcription factor regulated by hypoxia (hypoxia inducible factor). COX-2 activation and NO also increase VEGF synthesis.16 Increased VEGF has been observed in response to EGF, bFGF,  EGF, interleukin (IL)-1, IL-6, transforming growth factor (TGF)-?, and  hepatocyte growth factor (HGF). The mechanism by which these and other growth factors promote angiogenesis may be to increase VEGF synthesis.16 VEGF binds to its receptors on the surface of endothelial cells. There are 2 receptors for VEGF: Flt-1 and Flk-1/KDR. They are receptor tyrosine kinases that dimerize and become autophosphorylated upon VEGF binding.16-18 Activation of VEGF receptors initiates multiple intracellular downstream signaling pathways. Second messengers implicated in KDR signaling include phospholipase C, protein kinase C, the nonreceptor tyrosine kinase Src, ?v?5 integrins, phosphoinoside-3-kinase, and Ras and MAP kinase.16 Downstream signaling pathways in endothelial cells lead to inhibition of apoptosis, stimulation of mitosis, and cytoskeletal changes associated with motility.16,17 * * * * * * * * * * 肝细胞癌的靶向治疗：分子基础 HCC 的分子发病机制极其复杂 慢性HBV/HCV 感染或环境毒素引发肝硬化并诱导肝细胞基因水平的病变。 信号传导途径异常导致细胞异常增生及存活：