Loss of function mutations in the Neurofibromatosis type 1 (NF1) gene result in an autosomal dominant disease that affects 1:3500 live births. 95% of carriers will develop neurofibromas in their lifetime. Plexiform neurofibromas can cause disfigurement and/or compression of organs, which can have devastating physical and psychological consequences. Progression of plexiform neurofibromas to malignant peripheral nerve sheath tumors (MPNST) occurs in 8-13% of patients. Currently the only treatments for neurofibromas involve surgical removal of tumor tissue and of the affected nerve with or without cancer chemotherapy. Cancer therapies frequently trigger genomic instability, thus when used in young individuals they can induce mutations that will lead to malignancies later in life. Therefore, better treatments are needed for NF1 disease. Nf1 is a GTPase-activating protein (GAP) for Ras proteins and loss of NF1 results in increased levels of Ras-GTP, the activated form of Ras, which can lead to many of the phenotypes observed in NF1 patients. Loss of human NF1 leads to activation of PKA and MAPK pathways in Schwann cells contributing to the aberrant migration and proliferation of these cells. The budding yeast Saccharomyces cerevisiae has two NF1-like genes called IRA1 and IRA2 that when mutated lead to phenotypes that are reminiscent of Schwann cells with mutations in NF1. Expression of the catalytic domain of human NF1 can suppress the phenotypes of ira yeast mutants. The conservation of these pathways makes the genetically amenable yeast an excellent model system to use to identify drug targets for NF1. The work proposed here addresses two hurdles in the studies of NF1 and can only be achieved using a system such as yeast. The first hurdle is the lack of a system that allows identification of therapies specific to cells lacking NF1 and the second is the need for a resource amenable to high throughput analyses with which to carry out chemical screens. We propose to take a two-pronged approach by using two models, human cells and yeast for the identification of drug targets for NF1. There is no better model than the yeast for these types of screens, thus by combining these two models we present a powerful strategy for screening compounds to identify and validate potential drug targets for NF1.
NF1 is an inherited disease that affects 1:3500 live births in which 95% of carriers develop neurofibromas that include plexiform neurofibromas. Plexiform neurofibromas can cause disfigurement and/or compression of organs with devastating consequences. Despite the fact that NF1 is one of the most frequently inherited genetic disorders and that the gene involved in the disease is known, currently there is no effective pharmacological therapy for NF1. This proposal addresses two hurdles in the identification of therapies for NF1. The first hurdle is the lack of a system that allows identification of therapies specific to cells with NF1 mutations and the second is the need for a resource amenable to high throughput drug screens. The work proposed here takes a two-pronged approach using human cells and a genetic model system, the yeast for the identification of drug targets for NF1. There is no better model than the yeast for these types of screens, thus by combining these two models we present a powerful approach for screening compounds to identify and validate potential drug targets for NF1.
| Allaway, Robert J; Wood, Matthew D; Downey, Sondra L et al. (2018) Exploiting mitochondrial and metabolic homeostasis as a vulnerability in NF1 deficient cells. Oncotarget 9:15860-15875 |
| Wood, Matthew; Rawe, Melissa; Johansson, Gunnar et al. (2011) Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells. Mol Cancer Ther 10:1740-50 |
| Wood, Matthew D; Sanchez, Yolanda (2010) Deregulated Ras signaling compromises DNA damage checkpoint recovery in S. cerevisiae. Cell Cycle 9:3353-63 |
