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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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至关重要，是肿瘤扩张、生存和传播的限速过程1,2VEGFR-2激酶通常局限于肿瘤激活的内皮细胞和哺乳动物组织和器官的静止（非增殖）内皮细胞上的细胞表达最近，它已在选定的造血干细胞亚群中被确定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是肿瘤血管生成多个步骤的主要介质，包括内皮细胞增殖、存活、迁移、分化和血管通透性。细胞质催化结构域在配体结合时被自磷酸化激活，它负责底物磷酸化，介导肿瘤内皮细胞激活的这些多步骤的信号通路。在正常组织中，血管内皮生长因子（VEGF）仅在缺氧条件下上调，其mRNA稳定。相比之下，在肿瘤细胞中，VEGF是组成性过表达的，不受环境氧张力的影响，但它的表达可以在缺氧的情况下进一步增加，这在实体瘤中很常见最近也有临床验证了抑制VEGF通路产生的抗肿瘤活性。阿瓦斯汀是一种抗VEGF-A抗体，在转移性结直肠癌患者的化疗中添加阿瓦斯汀可显著提高生存率8，并延长肾癌患者的进展时间9BMS-540215是丙氨酸酯前药BMS-582664的化学母体和活性部分。它是一种选择性和有效的VEGFR-2底物磷酸化抑制剂，也对成纤维细胞生长因子受体（FGFR-1）有活性，FGFR-1是另一种重要的血管生成调节剂。通过抑制VEGFR-2和FGFR-1， BMS-540215及其口服前药可抑制内皮细胞活化。因此，它有望在血管生成依赖的人类疾病，如癌症和肿瘤转移的治疗中有治疗应用。由于大多数常见癌症中有很大一部分过度表达VEGF，因此靶向这一途径的药物的潜在活性是广泛的。基于临床前数据，BMS-582664具有治疗多种肿瘤的潜力，既可以作为单一疗法，也可以作为当前标准治疗的附加疗法。

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.