Antiastrocytoma natural products that target tumor cells with defects in the tumor suppressor neurofibromin

Astrocytic glyomas, the most common malignant form of brain cancer, are often unresponsive to the current treatment options. Patient prognosis is generally quite poor, with the 5-year survival rate for patients with glioblastoma multiforme (GMB) below 5%. People with neurofibromatosis type 1 syndrome (NF1) have a high predisposition to develop tumors, with benign gliomas and neurofibromas being the most frequent type, but malignancies such as astrocytomas and GMB are also common. The NF1 gene codes for neurofibromin, a rasGAP tumor suppressor protein that downregulates the RAS signaling pathway. Lack of functional neurofibromin leads to overactivation of the oncogenic RAS pathway, a critical step in the development of many tumors. A recently developed assay for materials that selectively target cells expressing mutant neurofibromin was used to screen extracts from the NCI Natural Products Repository. A number of extracts were active in this screen and subjected to detailed chemical study. Bioassay-guided fraction of these extracts, looking for compounds with antiproliferative activity targeting astrocytoma cells and not healthy astrocytes, will be described.