The working hypothesis of our laboratory remains there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment and thus these events can be efficiently targeted therapeutically. We have turned our focus to two pathways identified in our previous studies: function of the CAIR-1/BAG-3 stress chaperone protein and progranulin (GEP) growth and invasion factor for ovarian cancer. We just reported that BAG-3 has a protective effect on cell stress by abrogating proteosomal degradation of polyubiquitinated client proteins under geldanamycin drive, dependent upon presence of the BAG domain and thus interaction with Hsp70. In the process, we identified two potential mechanisms of regulation of BAG-3 stability. Ongoing work also is dissecting the partner proteins in BAG-3 downregulation of adhesion, motility, and cytoskeletal reorganization in malignant cells. Lastly, clinical correlative studies using immunohistochemistry are ongoing to assess the role of CAIR-1 expression in epithelial ovarian and endometrial cancers. Our work in ovarian cancer identified GEP as a growth and survival factor. Current results indicate that GEP production is regulated by pathways activated by G protein-coupled growth factors known to be active in ovarian cancer, LPA and endothelin through a cAMP/EPAC/MAPK pathway. Downregulation of GEP with neutralizing antibodies causes apoptosis of ovarian cancer cells. Production of GEP and its subsequent activity may be part of a signal amplification cascade in ovarian cancer and is a logical target for molecular therapeutics. A biotechnology collaboration has been initiated for molecular therapeutics targeting GEP. Clinical assessment showed a link between GEP expression in ovarian cancer malignant effusions and patient outcome. Thus, GEP and BAG-3 each have potential as molecular therapeutic targets in ovarian cancer and other solid tumors.
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