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.
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