Signal Transduction Targets for Pharmacological Intervention in Type I Neurofibromatosis.

摘要

This New Investigator Award has the objective of the identification of new pharmacological approaches to NF1 treatment. We will proceed through the following aims and hypotheses: 1. Role of the Ras/MAP kinase pathway in neurofibromin-deficient cells. Our hypothesis is that activation of the Ras 1 MAP kinase signaling system plays a critical role in the phenotypes of human neurofibrosarcomas. The experiments use 2 novel pharmacological approaches to inhibit the Ras/MAP kinase pathway: 3-allylfarnesol A NOVEL INHIBITOR OF PROTEIN FARNESYLATION and PD184352 A NEW-GENERATION INHIBITOR OF MEK1. We assay a variety of end-points in the cells, including the level of Ras-GTP loading, activation status of ERK MAP kinases, transcriptional reporter assays of Ras I MAP kinase-responsive genes, and rates of cellular proliferation. 2. Role of Rac/Rho family small GTPases in neurofibromin-deficient cells. We will examine the hypothesis that Rac/Rho small GTPases contribute to the NF1 phenotype by use of novel, selective inhibitors of protein geranylgeranylation, such as 3- allylgeranylgeraniol. These experiments should validate the use of two new classes of pharmacological inhibitors of the Ras I MAP kinase pathway in fibroblast systems that have aberrant Ras activation due to neurofibromin- deficiency. This project will thus lead to the identification of relatively non- toxic and mechanistically specific drugs, which could then be investigated in future clinical trials for chemoprevention of tumors and chemotherapy of malignancies in NF1 patients.