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).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010541-09
Application #
8349044
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2011
Total Cost
$124,555
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing et al. (2014) Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus. Cancer Res 74:7260-73
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
Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing et al. (2013) Resistance to oncolytic myxoma virus therapy in nf1(-/-)/trp53(-/-) syngeneic mouse glioma models is independent of anti-viral type-I interferon. PLoS One 8:e65801
Walrath, Jessica C; Hawes, Jessica J; Van Dyke, Terry et al. (2010) Genetically engineered mouse models in cancer research. Adv Cancer Res 106:113-64
Turbyville, Thomas J; G├╝rsel, Demirkan B; Tuskan, Robert G et al. (2010) Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Mol Cancer Ther 9:1234-43
Hawes, Jessica J; Reilly, Karlyne M (2010) Bioluminescent approaches for measuring tumor growth in a mouse model of neurofibromatosis. Toxicol Pathol 38:123-30
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