PNET EXPERIMENTAL THERAPEUTICS--ANTINEOPLASTIC AGENTS AND TREATMENT DELIVERY

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This Project pursues laboratory studies which address the need for effective new treatment strategies for medulloblastoma (MB) and related primitive neuroectodermal tumors (PNET). These studies emphasize the role of tyrosine kinase growth factors as targets for therapeutic intervention in PNET and establish a basis for extending new insights about the neurobiology of PNET into the clinical setting. Our primary focus will be new treatments for leptomeningeal (LM) dissemination of PNETs. This serious clinical problem has a profound negative effect on treatment outcome and survival. Moreover, the most effective current treatment for LM- PNET is craniospinal radiation therapy (RT), which causes severe cognitive impairment in many long-term survivors. Identification of effective alternatives which permit dose reduction or elimination of craniospinal RT is likely to improve the duration and quality of survival for these children. Our studies indicate that intrathecal (i.t.) administration of cytotoxic drugs, monoclonal antibodies, immunotoxins, and recombinant toxins has specific therapeutic advantages over systemic administration. Accordingly, this project will study the efficacy and toxicity of new agents administered regionally for the treatment of LM-PNET. In Aim 1, we will extend our studies of topoisomerase 1 (Topo 1) inhibitors to evaluate the neurotoxicity and therapeutic efficacy of i.t. treatment with camptothecin, a Topo 1 inhibitor, in a nude rat model of leptomeningeal MB. We will expand these studies by exploring potential synergistic interactions, identified by our in vitro cytotoxicity studies, between Topo 1 inhibitors and 4- hydroperoxy-cyclophosphamide. In Aim 2, we will investigate the neurotoxicity and efficacy of recombinant Pseudomonas exotoxin (PE) fused with acidic fibroblast growth factor, alone or in combination with transforming growth factor alpha-PE, for i.t. treatment in a nude rat model of leptomeningeal MB. In Aim 3, we will evaluate the neurotoxicity and efficacy of i.t. rapamycin, an inhibitor of insulin-like growth factor signal transduction, in a model of leptomeningeal MB. We will extend these studies in Aim 4 to identify factors which predict rapamycin sensitivity or resistance in MB. We anticipate that these studies will broaden the scope of PNET therapeutic strategies and will be applicable to other childhood and adult brain tumors.