靶向治疗在乳腺癌中的应用.ppt

* References Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512. Smith IE et al. Lancet 2007; 369: 29-36. * Listed are selected agents targeting the VEGF pathway that are in development Agents targeting the VEGF ligand Antibodies include Bevacizumab (Avastin?), which the FDA has designated as part of its Fast Track development program for the treatment of previously-untreated MCRC is currently in phase III clinical development in several tumor types, and recently completed a pivotal phase III trial in CRC which met its primary endpoint (improved survival) 2C3 is in preclinical development and inhibits VEGF interactions with VEGFR-2 but not VEGFR-1 VEGF-Trap—a recombinant soluble receptor that binds to both VEGF and PlGF Agents targeting VEGFRs Small molecule inhibitors include PTK-787, SU11248, and ZD6474 Many of these small molecules inhibit VEGFRs as well as other kinases Several antibodies that target either VEGFR-1 or VEGFR-2 are also in development Angiozyme utilizes a novel therapeutic approach, using an RNA enzyme to inhibit the synthesis of VEGFR-1 Currently, the agent in the most advanced stage of clinical development that targets the VEGF pathway is bevacizumab Eliceiri and Cheresh. Cancer J. 2000;6(suppl 3):S245. Hasan and Jayson. Expert Opin Biol Ther. 2001;1:703. Hennequin et al. J Med Chem. 2002;45:1300. Nelson et al. J Clin Oncol. 2000;18:1135. Leading to Endothelial cell survival, migration, proliferation, and vascular permeability * * * * * * Stratification Disease sites Bone only/visceral or soft tissue Interval since adjuvant tamoxifen therapy 6 months/≥6 months or none * 赫赛汀? 用于治疗HER2阳性乳腺癌 MBC：生存率提高达45% EBC：复发风险降低52％ 95% 人源化, 5% 鼠抗，具有高度亲和性 (Kd=0.1nM) 和特异性，显著降低免疫原性(HAMA) MBC, 转移性乳腺癌; EBC, 早期乳腺癌; HAMA:human anti-murine antibody 人抗鼠抗体 HER2 过度表达细胞 赫赛汀?与HER2受体结合 生长信号 被阻断 抑制肿瘤 细胞生长 作用机制 赫赛汀的研发历程 I期安全性临床研究开始 鼠 HER2 / neu 基因成功克隆 人 HER2 基因克隆 单抗4D5研发 发现HER2与临床预后差相关 紫杉醇 + 赫赛汀 和赫赛汀单药 适应症美国批准