A PHASE II RANDOMIZED, CROSS-OVER, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL O

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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. Neurofibromatosis 1 (NF1) is a common autosomal dominant, progressive genetic disorder with an incidence of 1:3000 (>80,000 persons affected in The United States). NF1 is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic manifestations with no standard drug treatment options available. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas (27%) optic gliomas gliomas (15-20%), pheochromocytomas (1%), malignant peripheral nerve sheath tumors (5%), and neurofibrosarcomas (6%). Plexiform neurofibromas are nerve sheath tumors that grow along the length of nerves and involve multiple branches of a nerve. They are a major source of morbidity, causing disfigurement, impairment of nerve function, and in some cases development of malignant peripheral nerve sheath tumors. Neurofibromin, the NF1 gene product, contains a domain with significant homology to ras GTPase-activating proteins (GAP). The ras proteins are integral in cell signaling pathways, and activation of ras leads to cell proliferation. GAPs catalyze the hydrolysis of ras-GTP (the active form of ras) to ras-GDP and lead to ras inactivation. Patients with NF1 have decreased levels of neurofibromin, which is associated with an activated ras-GTP status. Agents directed at inhibiting ras, therefore, are a rational choice for trials of potential therapeutic agents in patients with NF1 and progressive plexiform neurofibromas. Farnesylation is a post-translational modification in which a farnesyl isoprene group is added to a number of cellular proteins by the enzyme, farnesyl-protein transferase (FPTase). The ras family of G proteins is one of the classes of proteins that are modified by FPTase. H-, K-, and N-ras are 21 kDa guanine nucleotide-binding proteins that control a multitude of cell signaling events. Mutant ras genes have the ability to transform cells into a malignant phenotype, and ras mutations have been observed in approximately 30% of all human cancers. Patients with NF1 do not have germline ras mutations. However, tumor cell lines established from malignant schwannomas of NF1 patients have been shown to have a constituitively activated ras-GTP status. Neurofibromin, which is the product of the NF1 gene, contains a domain that shows significant homology to ras GTPase-activating proteins (GAP). In these cell lines, there are normal levels of GAP, but decreased levels of neurofibromin, supporting the role of the NF1 gene as a tumor suppressor gene. Advances in the understanding of ras oncoprotein function suggest novel points for anti-tumor intervention. Ras is synthesized as a cytosolic precursor that ultimately localizes to the cytoplasmic face of the plasma membrane after a series of post-translational modifications. The first obligatory step in this series of post- translational modifications is the addition of a farnesyl moiety. This modification is essential for ras function. FPTase appears to be an appropriate biochemical target for the development of inhibitors of post-translational processing of ras resulting in prevention of ras-mediated cellular transformation. R115777 is a potent and selective non-peptidomimetic inhibitor of FPTase both in vitro and in vivo. In several preclinical studies, R115777 was shown to inhibit the growth of H-ras, K-ras and N-ras transformed tumors. Pharmacokinetic analysis of oral R115777 has also been performed on plasma samples from 30 children (median age 13 years, age range 5 to 17 years) treated on our pediatric phase I trial. In general the pharmacokinetics of R1157777 are similar in adults and children.