PHASE I DOSE ESCALATION STUDY TO DETERMINE THE SAFETY,PHARMACOKINETICS AND

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。血管内皮生长因子受体-2(VEGFR-2)是一种细胞表面蛋白酪氨酸激酶受体，对调节肿瘤血管生成是必不可少的，这是肿瘤扩张、存活和扩散中的一个限速过程。1，2 VEGFR-2激酶通常仅限于在哺乳动物组织和器官的肿瘤激活的内皮细胞和静止的(非增殖的)内皮细胞上表达。3，4最近，它被发现存在于特定的造血干细胞亚群中。5 VEGFR-2是包括VEGFR-1和VEGFR-3.6在内的一个更大的受体家族的一部分。VEGFR-2是肿瘤血管生成中多步骤的主要介导者，包括内皮细胞增殖，血管内皮细胞生长存活、迁移、分化以及血管通透性。1、5、7、8.细胞质催化结构域在配体结合时被自动磷酸化激活，负责底物磷酸化，参与介导参与这些肿瘤内皮激活的多个步骤的信号通路。在正常组织中，血管内皮生长因子(VEGF)表达上调，其mRNA只有在低氧条件下才稳定。相比之下，在肿瘤细胞中，VEGF呈结构性过表达，与环境氧分压无关，但它的表达可因缺氧而进一步增加，这在实体肿瘤中普遍存在。2最近，也有临床证实抑制VEGF途径产生的抗肿瘤活性。阿瓦斯丁是一种抗血管内皮生长因子-A抗体，当加入化疗时，转移性结直肠癌患者的存活率显著增加8，肾癌患者的进展时间延长。9BMS-540215是丙氨酸酯前体药物BMS-582664的化学母体和活性部分。它是VEGFR-2底物磷酸化的选择性和有效的抑制剂，也有抗成纤维细胞生长因子受体(FGFR-1)的活性，成纤维细胞生长因子受体是另一种重要的血管生成调节因子。BMS-540215及其口服前药通过抑制血管内皮生长因子受体-2和成纤维细胞生长因子受体-1抑制血管内皮细胞的激活。因此，它有望在血管生成依赖的人类疾病中有治疗应用，如在癌症和肿瘤转移的治疗中。由于很大一部分最常见的癌症过度表达血管内皮生长因子，因此针对这一途径的药物的潜在活性是广泛的。根据临床前的数据，BMS-582664具有治疗多种肿瘤的潜力，既可以作为单一疗法，也可以作为当前护理标准的补充。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a cell surface protein tyrosine kinase receptor that is essential for regulating tumor angiogenesis, a rate limiting process in tumor expansion, survival, and dissemination.1,2 The VEGFR-2 kinase is generally restricted to cellular expression on both tumor activated endothelial cells and quiescent (non-proliferating) endothelial cells of mammalian tissues and organs.3,4 More recently, it has been identified in selected subsets of hematopoietic stem cells.5 VEGFR-2 is part of a larger family of receptors that include VEGFR-1 and VEGFR-3.6 VEGFR-2 is the major mediator of multiple steps in tumor angiogenesis that include endothelial cell proliferation, survival, migration, differentiation as well as vascular permeability.1,5,7,8. The cytoplasmic catalytic domain, which is activated by autophosphorylation upon ligand binding, is responsible for substrate phosphorylation implicated in mediating signaling pathways involved in these multiple steps of tumor endothelium activation. In normal tissues, vascular endothelial growth factor (VEGF) Is upregulated and its mRNA stabilized only under conditions of hypoxia. In tumor cells, by contrast, VEGF is constitutively overexpressed, independent of the ambient oxygen tension, but its expression can be further increased by hypoxia, which is commonly present in solid tumors.2 Recently there has also been clinical validation of the anti-tumor activity produced by inhibition of the VEGF pathway. Avastin¿, an anti- VEGF-A antibody, leads to a significant increase in survival when added to chemotherapy for subjects with metastatic colorectal cancer 8, and prolonged time to progression in subjects with renal cancer.9 BMS-540215 is the chemical parent and active moiety of the alanine ester prodrug BMS-582664. It is a selective and potent inhibitor of VEGFR-2 substrate phosphorylation and also has activity against fibroblast growth factor receptor (FGFR-1), another important regulator of angiogenesis. By inhibition of VEGFR-2 and FGFR-1, BMS-540215 and its orally available prodrug inhibit endothelial cell activation. Therefore, it is anticipated to have a therapeutic application in angiogenesis dependent human disease, such as in the treatment of cancer and tumor metastasis. Since a significant proportion of most common cancers overexpression VEGF, the potential activity of agents targeting this pathway is broad. Based on pre-clinical data, BMS-582664 has the potential for therapeutic use in a wide variety of tumors, both as monotherapy and as an add-on to the current standard of care.