Glioma Therapeutics Targeting Glioma Pathogenesis-related Protein

DESCRIPTION (provided by applicant): Gliomas are malignant tumors that arise from glial cells in the central nervous system and are among the deadliest of human cancers. These tumors are notorious for their aggressive and highly invasive behavior. Their ab ility to invade into the surrounding normal brain is unique to primary brain tumor cells and has made therapeutic intervention very difficult. It is hoped that greater understanding of the molecular mechanisms involved in glioma cell invasion and migration will lead to more effective targeted therapies soon. Attention is particularly focused on identifying novel membrane-associated and secreted proteins that are specifically upregulated in glioma cells and that could define new targets for the diagnosis and treatment of the disease. With the goal to develop a new therapy for human glioma, we propose to investigate the role of Glioma Pathogenesis-Related Protein (GliPR, also called RTVP-1), a membrane-associated protein that is overexpressed in glial tumors a nd glioma-derived cell lines. GliPR expression in those cells correlates with metalloprotease MMP2 secretion and activation and increased invasiveness. Although GliPR's exact function is unknown, it is structurally related to a family of PR-1 proteins, whi ch are characterized by a highly conserved 15-16 kDa cysteine-rich PR-1 domain thought to play a role in PR-1 function. Functions of proteins of this family range from ion-channel blockers to serine proteases and chemoattractants. Our hypothesis is that Gl iPR may serve as a novel therapeutic target in the treatment of gliomas. Evidence was recently obtained that GliPR plays a role in the highly invasive character of gliomas in correlation with metalloprotease MMP2 activation. Therefore we propose that funct ional antibodies specifically targeting the native form of GliPR could reduce glioma invasive behavior by selectively modulating MMP2 activation. The goal of this Phase I project is to validate GliPR as a valid therapeutic target in glioma pathogenesis by identifying functional polyclonal antibodies that inhibit glioma invasiveness, and to test if those antibodies also inhibit MMP2 activation. The specific aims of this Phase I proposal are: 1) Express and purify soluble truncated recombinant GliPR (rGliPR) protein in a Pichia eukaryotic expression system. 2) Produce and characterize anti-GliPR antibodies that recognize native epitopes of the protein. 3) Demonstrate that anti-GliPR antibodies inhibit invasiveness in vitro and test if they reduce MMP2 activati on. In the Phase II of this project, we expect to develop candidate therapeutics directed against GliPR, such as monoclonal antibodies and/or small molecule inhibitors, and evaluate them in murine intracranial models for glioma. The long term goal is to pr oduce therapeutics that will inhibit glioma progression in patients and that could be administrated intracranially in combination with other targeted therapies that would kill cancer cells. PUBLIC HEALTH RELEVANCE: Gliomas are malignant tumors that arise f rom glial cells in the central nervous system and are among the deadliest of human cancers. Our project is designed to develop new therapeutics to combat the highly aggressive and invasive malignant behavior of brain tumors.