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 2012 we collaborated with the Molecular Targets Laboratory to purify compounds from natural product extracts with anti-NF1/astrocytoma activity. Compounds were analyzed in a primary screen for their ability to inhibit the growth of Nf1/p53 mutant mouse anaplastic astrocytoma cells and in a secondary screen to identify compounds that inhibited both mouse and human brain tumor cells compared to normal cultured brain cells. We identified 3 very promising candidate compounds that inhibited all tumor cells, but not normal cells, 6 candidates with specific activity against particular tumor cell lines that may show specificity for certain subtypes of brain cancer, and 6 compounds that inhibit growth of both tumor cells and normal brain cells, which may be developed further into more specific drugs through chemical modification or delivery methods. Many compounds with closely related chemical structures were found to be inactive, giving us an early indication of the structure-activity relationships between these molecules.In another collaboration with the Molecular Targets Laboratory, we are examining the effects of a natural compound, schweinfurthin, on astrocytoma and MPNST in vitro and in vivo. We have shown that schweinfurthin inhibits multiple NF1-associated tumor types. The in vitro work was published in Molecular Cancer Therapeutics (Turbyville et al 2010) and we are continuing our efforts in vivo. In fiscal year 2012 we collaborated with investigators at University of Iowa to synthesize close to 1 g of pure synthetic schweinfurthin, and have been testing the pharmacokinetic properties of the new batch of compound in preparation for larger in vivo studies for the efficacy of schweinfurthin.
