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 (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 2011 we completed primary and secondary high-throughput screening of compound libraries available at NCI. We identified interesting new classes of compounds synthesized by a group at Boston University and a group in Rome that have not been studied for cancer previously and are pursuing their specificity and mechanism of action. In collaboration with the Molecular Targets Laboratory we are fractionating and testing activity of natural product extracts to identify new active compounds against astrocytoma. We have also continued our collaboration with a clinical NF group at Children's National Medical Center to take promising therapeutic leads for testing in our Nf1/p53 mouse model. 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 2011 we tested three schweinfurthin analogues in vivo and determined that one showed a log-fold higher level in serum. Furthermore, this analog crosses the blood-brain barrier and may accumulate in the brain up to 2 hours after injection. We are continuing our studies focused on this lead compound. We used this compound in an efficacy trial of schweinfurthin against subcutaneous grafts of MPNST cells and found that tumor growth was significantly inhibited (manuscript in preparation).
