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. This is a multicenter, Phase I trial to estimate the maximum tolerated dose and describe dose limiting toxicities of enzastaurin (LY317615) administered orally for 28 consecutive days to children and adolescents with refractory primary CNS tumors. Pharmacokinetic, imaging and biology correlative studies will be performed in all consenting patients. Enzastaurin will have anti-tumor activity in children and adolescents with refractory primary CNS tumors. Central nervous system tumors (CNS) are the most common solid malignancy of childhood and the second most common pediatric cancer. There are approximately 2000 new childhood brain tumors diagnosed each year. There have been modest improvements in the treatment of childhood CNS tumors over the past several decades using multi-modality therapy including surgery, radiation and chemotherapy. Nevertheless, deaths caused by CNS tumors are the highest among pediatric cancers. In addition, the morbidity associated with CNS tumors and currently available therapeutic strategies may be profound with regard to physical deficits as well as neuro-psychological and neuroendocrine sequelae. Thus, new agents and treatment strategies are needed for the effective treatment of these challenging malignancies. Neovascularization is important for tumor growth and metastases and therefore chemotherapeutic agents that inhibit angiogenesis pathways are an important emerging class of agents that warrant further study and characterization in pediatric patients with malignancies. Studies of the role of angiogenesis in CNS tumors from both children and adults have shown that there is marked angiogenic activity in astrocytic as well as embryonal tumors. In some studies, the degree of angiogenesis inversely correlates with patient survival, particularly for patients with high-grade tumors. In addition, preliminary studies evaluating VEGF concentrations in the cerebrospinal fluid of patients with leptomeningeal metastasis reveal that CSF VEGF levels mirror the patient's clinical course with a marked reduction in response to therapy and an increase at relapse. This suggests that markers of angiogenesis may serve as predictors of response to therapy and outcome.
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