Type 1 neurofibromatosis (NF1) is a common genetic disorder that is characterized by abnormal cell proliferation of neuroectodermal tissues. Benign neurofibromas arise in nearly all NF1 patients, and there is increased risk of neurofibrosarcomas and other malignant tumors. There is no current therapy to prevent the occurrence of tumors, and standard therapy of the tumors that do arise is limited. The NF1 gene, a candidate tumor-suppressor gene, encodes a protein called neurofibromin. Neurofibromin is a large protein that functions in part to decrease the levels of the active form of Ras proteins. Ras proteins are key regulators of cell signaling pathways and cell growth. Mutant, permanently activated Ras proteins are frequently found in many types of human tumors. In accord with this role of neurofibromin, increased activity of the Ras-driven growth pathway has been noted in cells derived from NF1 patients. However, the detailed mechanism of this growth stimulation has not been determined.

This proposal for a New Investigator Award will bring together the expertise of five independent laboratories (one junior investigator and four established scientists, all new to the NF1 field). Our objective is to define new pharmacological approaches to NF1 treatment and cancer prevention. Using NF1 gene deficient cells as models, we will test how this insufficiency triggers an increased proliferative signal to cells. We will determine in molecular detail how a deficiency in neurofibromin leads to abnormal cell growth. Furthermore, we will define the role of growth factors generated by NF1-deficient fibroblasts in stimulating the growth of Schwann cells. Since both fibroblasts and Schwann cells are found in human neurofibromas, this particular study is relevant to the development of the disease in humans. These basic insights gained into neurofibroma growth will then be used in further, more clinically relevant pharmacological studies with cells from NF1-deficient mice and with cultured human neurofibroma cells. We will attack specific points in the growth stimulation pathway with drugs targeted to known elements of the overall pathway. A successful drug will be one that results in growth inhibition of the NF1 deficient cells and less so to the cells with normal NF1 genes. This project thus will lead to the identification of relatively nontoxic and mechanistically specific drugs, which could then be investigated in clinical trials for chemoprevention of tumors and chemotherapy of malignancies in NF1 patients.