PHASE I STUDY OF CILENGITIDE (EMD 121974) IN CHILDREN WITH REFRATORY BRAIN TUMOR

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。血管生成是肿瘤生长的关键，由肿瘤分泌的血管生长因子诱导，这些因子激活并促进内皮细胞增殖、存活和成熟。这种活化的结果之一是整合素受体在内皮细胞上的表达，其存在似乎对内皮细胞的持续存活和增殖以及侵袭至关重要。两种特异性整合素，α v β 3和α v β 5受体，似乎在血管生成过程中特别重要，因此代表了开发用于治疗恶性肿瘤的抗血管生成策略的逻辑靶点。这些受体允许内皮细胞通过它们与基质蛋白上发现的RGD序列结合的能力附着到细胞外基质。因此，抑制血管生成的一种方法是使用含RGD的肽拮抗剂。对α v β 3和α v β 5受体的特异性可通过环化RGD肽显著增强。Cilengitide（EMD 121974）是环化的RGD五肽（cyclo-[Arg-Gly-Asp-DPhe-（NMeVal）]）的内盐，是有效的和选择性的α v β 3和α v β 5玻连蛋白受体拮抗剂。已显示其在多种体内系统中以剂量依赖性方式抑制肿瘤生长。 难治性CNS肿瘤儿童的治疗计划将包括每周两次给予西仑吉肽，每次1小时输注，持续长达一年，无不可接受的毒性或肿瘤进展。基于正在进行的西仑吉肽研究的新数据，这些研究在较高剂量范围内继续显示出可接受的毒性特征，即使在较低剂量范围内也有临床获益的潜力，本研究可能会研究更广泛的剂量范围。

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. Angiogenesis, which is critical for tumor growth, is induced by tumor secretion of vascular growth factors that activate and promote endothelial cell proliferation, survival, and maturation. One of the consequences of this activation is the expression on endothelial cells of integrin receptors, whose presence appears to be crucial for continued survival and proliferation of and invasion by endothelial cells. Two specific integrins, the alpha v Beta 3 and alpha v beta 5 receptors, appear to be particularly important in the process of angiogenesis, and therefore represent logical targets for the development of anti-angiogenesis strategies for the treatment of malignancies. These receptors allow endothelial cells to attach to the extracellular matrix through their ability to bind to RGD sequences found on the matrix proteins. Thus, one approach to inhibiting angiogenesis is to use RGD-containing peptide antagonists. Specificity for the alpha v beta 3 and alpha v beta 5 receptors can be significantly enhanced by cyclizing RGD peptides. Cilengitide (EMD121974), the inner salt of a cyclized RGD pentapeptide (cyclo-[Arg-Gly-Asp-DPhe-(NMeVal)], is a potent and selective alpha v beta 3 and alpha v beta 5 vitronectin receptor antagonist. It has been shown to inhibit tumor growth in a dose dependent manner in a variety of in vivo systems. The treatment plan for children with refractory CNS tumors will consist of administration of cilengitide twice weekly as a 1-hour infusion for up to one year in the absence of unacceptable toxicity or tumor progression. Based on emerging data from ongoing studies with cilengitide, which continue to show acceptable toxicity profile at the higher dosing range and potential for clinical benefit even at the lower dosing range, this study will potentially investigate a broad range of doses.