The working hypothesis of our laboratory posits 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 granulin-epithelin precursor (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. This was dependent upon presence of the BAG domain, indicating a requirement for interaction with Hsp70. Further studies are dissecting other components of this complex. Ongoing work is also addressing the role of BAG-3 in invasion and metastatic behavior at the cellular level in order to understand xenograft studies of the mutants that demonstrate differential phenotypes in vivo. Lastly, clinical correlative studies using immunohistochemistry are ongoing to assess the role of CAIR-1 expression in epithelial ovarian and endometrial cancers. Pathway regulation studies in ovarian cancer have identified GEP as differentially expressed between invasive ovarian cancer and tumors of low malignant potential. Antisense transfection was associated with reduced proliferation, cloning capacity, and survival pathway activation. 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. Thus, production of GEP and its subsequent activity may be part of a signal amplification cascade in ovarian cancer activation. A biotechnology collaboration has been initiated for molecular therapeutics targeting GEP. Clinical correlates are underway to assess GEP expression by immunohisto- and immunocyto-chemistry of patient malignant effusions and ascites and related tissue samples. Thus, GEP and BAG-3 each have potential as molecular therapeutic targets in ovarian cancer and other solid tumors.
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