A PHASE I TRIAL OF CC-5013 (LENALIDOMIDE) IN PEDIATRIC PATIENTS WITH RECURREN

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。复发和难治性中枢神经系统肿瘤的儿童患者预后非常差。许多肿瘤，包括几种类型的儿童中枢神经系统肿瘤，已经显示出肿瘤生长对血管生成的依赖，表现出强烈的新生血管并产生强大的血管生成介质。此外，血管生成的程度已被证明与患有高级别肿瘤的儿科患者的存活率呈负相关。在过去的十年里，已经阐明了几种参与肿瘤诱导血管生成的机制。其中最直接的是肿瘤细胞分泌具有血管生成特性的细胞因子。肿瘤细胞还可以通过产生蛋白水解酶和随后分解储存某些细胞因子的细胞外基质(如bFGF)来释放血管生成肽，或通过招募炎症细胞(特别是巨噬细胞)并随后释放血管生成细胞因子(如肿瘤坏死因子-α、碱性成纤维细胞生长因子)间接诱导血管生成。CC-5013是一种有效的沙利度胺类似物，具有广泛的药理、抗血管生成和免疫学作用。研究表明，CC-5013在T细胞受体激活的初次诱导后，在刺激T细胞的增殖方面比沙利度胺更有效，在TCR激活PBMC(IL-2)或T细胞(IFB-g)后，CC-5013比沙利度胺更有效地促进IL-2和干扰素-g的产生。CC-5013还呈剂量依赖性地抑制内毒素刺激的PBMC产生促炎细胞因子TNF-a、IL-1b和IL-6，而增加内毒素刺激的PBMC产生抗炎细胞因子IL-10。CC-5013在多发性骨髓瘤和胶质瘤患者的成人研究中耐受性良好。剂量限制性毒性似乎是骨髓抑制。CC-5013尚未在儿童中进行研究。

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. Pediatric patients with recurrent and refractory malignant CNS tumors have a very poor prognosis. Many tumors, including several types of childhood CNS tumors have shown a dependency on angiogenesis for tumor growth, demonstrating intense neovascularization and producing potent angiogenic mediators. In addition, the degree of angiogenesis has been shown to inversely correlate with survival in pediatric patients with high-grade tumors. Over the last decade, several mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these is the secretion by tumor cells of cytokines with angiogenic properties. Tumor cells can also release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (i.e. bFGF), or induce angiogenesis indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (i.e., TNF-a, bFGF) CC-5013 is a potent analog of thalidomide that exerts a broad spectrum of pharmacologic, antiangiogenic, and immunologic effects. CC-5013 has been shown to be more potent than thalidomide in stimulating proliferation of T cells following primary induction by T-cell receptor activation, and more potent than thalidomide in augmenting production of IL-2 and IFN-g following TCR activation of PBMC (IL-2) or T cells (IFB-g). CC-5013 also exhibits dose-dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF-a, IL-1b, and IL-6 by PBMC, and increased production of the anti-inflammatory cytokine IL-10 by LPS-stimulated PBMC. CC-5013 has been well tolerated in adult studies of patients with multiple myeloma and glioma. The dose-limiting toxicity appears to be myelosuppression. CC-5013 has not yet been studied in children.