Astrocytoma is currently incurable due to its diffuse infiltration and the lack of effective therapies. We have developed a mouse model of spontaneous astrocytoma through mutation of Nf1 and p53. Both Nf1 and p53 have been shown to be mutated in sporadic human glioblastomas (GBM). In addition, p53 has been shown to be mutated in anaplastic astrocytomas, although NF1 has not yet been examined. In addition, Nf1 is associated with the disease neurofibromatosis type 1 (NF1), for which there are no cures and very few therapy options for treatment. The astrocytomas and GBM in the Nf1/p53 mutant mice show diffuse infiltration throughout the central nervous system and form secondary structures around neurons and blood vessels recapitulating the pathology seen in human astrocytomas. We are developing methods for using this model for testing experimental therapeutics. During fiscal year 2014 we used supplemental funding from the Drug Development Collaborative to test the effects of a natural compound, schweinfurthin in vivo. We continued our work on the maximum tolerated dose of schweinfurthin during multiple dosing and are developing an orthoscopic in vivo model of MPNST for testing the efficacy of schweinfurthins in vivo. We are also continuing our screen to look for enhancers and suppressors of schweinfurthin activity in human MPNST cells. Analysis of this screen will help us determine the direct target of schweinfurthin, in addition to learning a great deal about the biology of MPNSTs more generally.
