Malignant glioma is the most common primary central nervous system tumor in children and adults. Long-term disease free survival for patients with recurrent or progressive glial tumors treated with conventional therapy (radiotherapy | surgery) remains very poor. Although the addition of adjuvant chemotherapy has led to improvements in survival, long-term progression free survival in children with high- grade gliomas remains less than 50%. The primary objective of this project is to develop novel agents for the treatment of pediatric tumors of the nervous system, including agents capable of inducing differentiation, employing pre-clinical and clinical pharmacokinetic studies to optimize phase 1 and 2 trial designs. Experimental evidence suggest that certain pediatric malignancies, most notably neuroblastoma and glial cell tumors, may be prime targets for a differentiation-based approach to therapy. We are currently studying phenylacetate, a deaminated metabolite of phenylalanine which, in vitro, induces differentiation in a variety of glial cell lines. A pediatric phase I trial and pharmacokinetic study of phenylbutyrate in children with refractory cancer is being performed. Phenylbutyrate is rapidly converted in vivo to phenylacetate by mitochondrial beta-oxidation in the liver and kidneys, and appears to have molecular activities that are distinct from phenylacetate. The retinoids are capable of inhibiting cell growth and inducing differentiation in experimental tumor models including a number of pediatric tumor cell lines. Recently, all-trans-retinoic acid (ATRA) has been demonstrated to induce complete remissions in patients with acute promyelocytic leukemia (APL). Pharmacokinetic studies performed in adults and children demonstrated that with daily administration of ATRA, plasma concentrations decrease significantly over time, a phenomenon initially suspected of contributing to disease relapse in patients with APL. In pre-clinical pharmacokinetic studies, we demonstrated that ATRA was eliminated by a capacity-limited (saturable) mechanism, and determined that an intermittent schedule of drug administration could overcome the rapid decline in plasma drug concentration and provide repetitive periods of higher plasma drug exposure. We then demonstrated in adult and pediatric clinical trials that intermittent schedules of ATRA administration result in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. A phase 2 study of ATRA and IFN-alpha2a for children with refractory neuroblastoma and Wilms tumor is currently in progress. We are also studying 9-cis-retinoic acid (9cRA), a naturally occurring retinoid capable of binding and transactivating both the retinoic acid receptors and the retinoid X receptors. A pediatric phase I trial of 9cRA administered on a continuous three times daily oral schedule has been completed. Another agent targeting tumors of the nervous system being evaluated is SU101, a small synthetic compound that inhibits PDGF receptor mediated cell signaling. The effects of SU101 on the inhibition of cell growth has been tested in in vitro and in vivo models using a spectrum of human tumor cell lines. Sensitive cell lines include gliomas and neuroblastoma. Pharmacokinetic studies of SU101 in adults revealed an unexpectedly long half-life of approximately 14 days. The weekly dosing regimens used in adult studies have limited the ability to accurately perform pharmacokinetic modeling, and the scheduling frequency chosen may be unnecessary for maintaining significant concentrations of the active metabolite SU0020. We are therefore performing a pediatric phase 1 trial and pharmacokinetic study of SU101 administered as a 96 hour infusion every 21 days. - differentiation, brain tumors, retinoids, - Human Subjects: Minor under 18 Years Old
