Malignant gliomas are the most commonly occurring cerebral neoplasms in humans. The incidence of primary brain tumors is 16,000 cases annually, with malignant gliomas (glioblastoma multiforme) comprising 20-40% of these cases. Despite concentrated research efforts, the outlook for glioma patients remains grim. Approximately 90% of all glioma patients die within two years of diagnosis. This proposal examines the use of glial antiproliferative factors derived from Schwann cells (SC) or synthesized by SC proteases for treatment of malignant gliomas. Studies to determine the mechanisms underlying the cessation of SC proliferation in vitro have demonstrated that SC conditioned medium (CM) inhibits glia cell proliferation in vitro. This antiproliferative activity results following production of a 55 kD protein by SCs. This protein is a Zn++ metalloprotease which acts on fibronectin to produce 29 kD heparin-binding fibronectin fragments, which also inhibit in vitro primary glial cell and glioma proliferation. The experiments in the present proposal will evaluate the ability of the 29 kD protein, termed glial antiproliferative protein (GAP), to inhibit glial tumor cell proliferation and growth in vitro and in vivo . In Phase 11, drug formulation and the use of GAP in combination with resection, radiation, and chemotherapy for treating glioblastomas will be examined.
