The present invention is based, at least in part, on the discovery that Astrocyte Elevated Gene-1 (`AEG-1`) expression (i) suppresses the Excitatory Amino Acid Transporter-2 (`EAAT-2`) promoter, thereby inhibiting glutamate transport; (ii) supports anchorage independent colony formation of cells, in which it is synergistic with the RAS oncogene; and (iii) is increased in a number of different malignancies. The invention, in various embodiments, provides for methods of treatment of malignancies and neurodegenerative disorders using inhibitors of AEG-1 activity, and provides for screening assays for identifying other compounds that have therapeutic benefit.