PNET EXPERIMENTAL THERAPEUTIC--NEW ANTINEOPLASTIC AGENTS AND DRUG DELIVERY

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Studies to identify new antineoplastic agents for clinical use in primitive neuroectodermal tumors (PNET) are justified by the sensitivity PNETs have shown to various drug therapies, the success of preclinical laboratory studies in predicting PNET clinical response, and the persistence of treatment failures despite intensive adjuvant regimens. To evaluate new approaches to the problems of local and leptomeningeal (CSF) tumor control, we propose preclinical laboratory studies of two classes of new antineoplastic agents: (1) Transforming Growth Factor-alpha-pseudomonas exotoxin (TGF-alpha-PE), a recombinant toxin in which TGF-alpha, the epidermal growth factor receptor substrate, is fused with a genetically modified pseudomonas exotoxin; (2) Topoisomerase I inhibitors, including camptothecin, topotecan and other newly developed analogs. These agents have potential advantages for brain tumor therapy that have not been systematically evaluated. In Aim 1, we will evaluate the toxicity, pharmacology and efficacy of intrathecal TGF-alpha-PE for the treatment of PNET leptomeningeal metastases. We will employ the same research design that we used to develop intrathecal 4-hydroperoxy-cyclophosphamide for current phase I clinical trials. In Aim 2, we will study the toxicity and efficacy of TGF-alpha-PE incorporated into sustained-release biodegradable polymers for the treatment of local intracranial tumors. These investigations represent a continued collaboration with Dr. Henry Brem (Johns Hopkins University) on the application of this innovative approach to local drug delivery in brain tumors. Aims 3 and 4 will evaluate the potential use of topoisomerase I inhibitors for PNET therapy and will address the preclinical testing and identification of biochemical predictors of response to these agents. We anticipate that these studies will have broad applicability to the treatment of other childhood and adult primary brain tumors.