This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT HYPOTHESIS We hypothesize that anti-angiogenic agents will play a role in the treatment of children with central nervous system tumors.
SPECIFIC AIMS Primary objectives1.1 To estimate the MTD of oral CC-5013 administered to children with recurrent or refractory primary CNS tumors once daily for 21 days of a 28 day course.1.2 To describe the toxicity profile and define the dose-limiting toxicity of CC-5013 in children with recurrent or refractory primary CNS tumors.Secondary objectives1.3 To characterize the pharmacokinetics of CC-5013 in children and adolescents.1.4 To characterize the pharmacogenetics of CC-5013 in children and adolescents.1.5 To evaluate changes in circulating endothelial cells (CECs), circulating endothelial cell precursors (CEPs) in patients treated with CC-5013, and to investigate the correlation between changes in CECs and CEPs, plasma, serum and urine levels proteins associated with angiogenesis including thrombospondin, b-FGF, TNF-alpha, IL-12, IL-8 and VEGF, and correlate these changes with changes in MR perfusion and clinical outcome.1.6 To evaluate changes in MR spectroscopy, MR perfusion and diffusion during treatment.III. BACKGROUND AND SIGNIFICANCE Brain tumors are the most common solid tumors of childhood, with an annual incidence of 33 per 1,000,000 children. The overall 5-year survival rate for childhood brain tumors is ~73%1, but for children with refractory and recurrent malignant tumors, this number is much lower. The first line of treatment for most primary brain tumors is surgery and radiation, yet these modalities alone are rarely curative for malignant tumors. Malignant tumors are frequently infiltrative, and local therapy alone is not sufficient to eradicate all tumor cells. The tumors tend to recur after surgery or local radiation. Treatment options are limited for patients with recurrent or progressive disease. Some childhood CNS tumors have demonstrated sensitivity to chemotherapy,2-4 therefore, chemotherapy may be a means to treat those cells that escape local therapy. Chemotherapy is currently used as adjunctive treatment for malignant primary tumors, progressive benign tumors, and recurrent or resistant tumors. However, there are numerous obstacles or difficulties in attempting to treat CNS tumors with chemotherapy, including a limited number of available chemotherapeutic agents available, drug resistance, and delivery of drug to CNS tumors. New agents directed against novel cellular targets are needed.Angiogenesis in Childhood CNS TumorsAngiogenesis plays a role in tumor growth, including growth of tumors of the CNS. Brain tumors have demonstrated intense neovascularization5 and produce potent angiogenic mediators6,7. Several types of childhood CNS tumors, including low-grade astrocytic, high-grade astrocytic, and embryonal tumors exhibit significant angiogenic activity8,9. In addition, the degree of angiogenesis has been shown to inversely correlate with survival in pediatric patients with high-grade tumors10.Over the last decade, several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor11, angiogenin12, vascular endothelial growth factor (VEGF)13, and tumor necrosis factor alpha (TNF-a)14. Alternately, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored. Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines. Tumors can therefore use a number of different mechanisms to initiate and propagate neovascularization.ThalidomideThalidomide is a drug initially developed as a sedative, but subsequently found to have immunomodulatory and anti-angiogenic properties. It inhibits growth factor-mediated neovascularization, is a known inhibitor of tumor necrosis factor-a, and has demonstrated inhibition of tumor growth in solid tumor models. Thalidomide has the ability to costimulate T cells in vitro, inducing cytokine production, including IL-2 and IFN-?, and cytotoxic responses.15 Thalidomide has also been studied in multiple myeloma, a disease associated with increased bone marrow angiogenesis16, and was able to induce responses in 32% of patients with refractory multiple myeloma.17 Clinical trials of this agent in adults with recurrent high-grade gliomas have been performed,18,19 with some anti-tumor activity observed (4/36 objective radiographic responses in one study, with 12/36 SD for minimum of 2 months18), although the overall response rate was low.CC-5013CC-5013 is a potent analog of thalidomide which is under development for potential use in patients with multiple myeloma, myelodysplastic syndromes, Crohn's disease, congestive heart failure, and solid tumors. Like thalidomide, it exerts a broad spectrum of pharmacologic and immunologic effects. It is an immunomodulatory agent that inhibits the release of proinflammatory cytokines, promotes release of anti-inflammatory cytokines, and effects T cell proliferation. CC-5013 has been shown to be 50-100 times more potent than thalidomide in stimulating proliferation of T cells following primary induction by T-cell receptor activation (TCR), and 50-100 times more potent than thalidomide in augmenting production of IL-2 and IFN-? following TCR activation of PBMC (IL-2) or T-cells (IFN-?). CC-5013 also exhibits dosedependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF-a, IL- 1 , and IL-6 by PBMC, and increased production of the anti-inflammatory cytokine IL-10 by LPS-stimulated PBMC.
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