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 2013 we collaborated with the Molecular Targets Laboratory to test the specificity of compounds purified from natural product extracts with anti-NF1/astrocytoma activity. Compounds were analyzed in a tertiary screen for their ability to inhibit the growth of a panel of mouse and human brain tumor cells compared to normal cultured brain cells. We have narrowed our focus to 2 very promising candidate compounds that inhibited most tumor cells, but not normal cells. 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 2013 we tested the pharmacokinetic properties of the new batch of compound in preparation for larger in vivo studies for the efficacy of schweinfurthin. We also designed a screen of approximately 2200 genes using siRNA knockdown 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.
|Devkota, Krishna P; Wilson, Jennifer; Henrich, Curtis J et al. (2013) Isobutylhydroxyamides from the pericarp of Nepalese Zanthoxylum armatum inhibit NF1-defective tumor cell line growth. J Nat Prod 76:59-63|
|Hawes, Jessica J; Nerva, John D; Reilly, Karlyne M (2008) Novel dual-reporter preclinical screen for antiastrocytoma agents identifies cytostatic and cytotoxic compounds. J Biomol Screen 13:795-803|
|Reilly, Karlyne M; Rubin, Joshua B; Gilbertson, Richard J et al. (2008) Rethinking brain tumors: the fourth Mouse Models of Human Cancers Consortium nervous system tumors workshop. Cancer Res 68:5508-11|