Modeling Precursor Lesions by Targeting Key Molecular Pathways in High-Grade Serous Ovarian Cancer
thesisposted on 01.07.2016, 00:00 authored by Dimple A. Modi
High-Grade Serous Ovarian Cancer (HGSC) is the deadliest gynecological malignancy that affects women worldwide. A major confounding factor in the field is that the epithelial subtype responsible for HGSC is unclear and could either be the ovarian surface epithelium (OSE) or the fallopian tube epithelium (FTE) or both. Regardless of organ site, elevated levels of gonadotropin hormones are associated with increased incidence of ovarian cancer. Gonadotropins increased proliferation in both 3D ovarian organ culture and in a 2D normal mouse OSE cell line. Activation of pathways, such as Akt, EGFR, Birc5, Cdk2, Cdk4, and Cdkn2a identified in the 3D organ cultures, were also validated in 2D MOSE cells. Akt and EGFR inhibitors blocked gonadotropin-induced cell proliferation in 3D organ and 2D cell culture. These data suggested that the gonadotropins stimulate some of the same proliferative pathways in normal OSE that are activated in ovarian cancers. Rapid advances have been made in modeling serous pathogenesis from the FTE. However, the existing models fail to recapitulate the molecular basis of early precursor lesion development from the FTE. Loss of PAX2 is one of the earliest reported changes identified in the FTE that may define the transition of the normal FTE into benign lesions. Combination of PAX2 loss and mutant TP53 in murine oviductal epithelium (MOE) cells altered functional characteristics in vitro but was insufficient to drive tumorigenesis in vivo. Re-expression of PAX2 in PAX2-null human HGSC cells reduced tumorigenic properties via apoptosis. Reduced levels of PTEN negatively regulated PAX2 expression in MOE cells and stable re-expression of PAX2 reduced the tumorigenic effects from PTEN silencing. A novel biological screen identified a molecule that can activate PAX2 expression in MOE cells. A novel targeted delivery system conjugated to Follicle Stimulating Hormone (FSH) peptide was designed to specifically target FSH receptor in ovarian cancer cells. The selectivity of the FSH-targeted dendrimers was validated in 3D ovarian organ cultures, in vivo and in a HGSC cell line. In summary, it is critical to determine the mechanism of early precursor formation and design delivery systems to accurately target ovarian cancer cells.