Astrocytoma is currently incurable due to its diffuse infiltration and the lack of effective therapies. We are developing 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, 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 imaging astrocytomas in live animals and quantitating tumor burden in order to use this model for testing experimental therapeutics. During fiscal year 2009 we developed our collaboration with the Molecular Targets Development Program to use this assay for high-throughput screening of compound libraries available at NCI. In another collaboration with the Molecular Targets Development Program, we are examining the effects of a natural compound, Schweinfurthin, on astrocytoma in vitro and in vivo. We have shown that Schweinfurthin inhibits multiple NF1-associated tumor types. We have tested additional Schweinfurthin analogues that amy provide better stability in vivo and have developed a better formulation for in vivo testing. We have also continued our collaboration with a clinical NF group at Children's National Medical Center to perform cross-species comparisons of NF1 tumor cells and to take promising therapeutic leads for testing in our Nf1/p53 mouse model.
