(Georgia Institute of Technology, 2010-01-11)
Dickerson, Erin B.; Blackburn, William H.; Kapa, Laura B.; Lyon, L. Andrew; McDonald, John F.
Background.
Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such as the epidermal growth factor receptor (EGFR), which has been shown to increase the sensitivity of cancer cells to taxane chemotherapy. However, delivery represents the main hurdle for the broad development of RNAi therapeutics.
Methods.
We report here the use of core/shell hydrogel nanoparticles (nanogels) functionalized with peptides that specially target the EphA2 receptor to deliver small interfering RNAs (siRNAs) targeting EGFR. Expression of EGFR was determined by immunoblotting, and the effect of decreased EGFR expression on chemosensitization of ovarian cancer cells after siRNA delivery was investigated.
Results.
Treatment of EphA2 positive Hey cells with siRNA-loaded, peptide-targeted nanogels decreased EGFR expression levels and significantly increased the sensitivity of this cell line to docetaxel (P < 0.05). Nanogel treatment of SK-OV-3 cells, which are negative for EphA2 expression, failed to reduce EGFR levels and did not increase docetaxel sensitivity (P > 0.05).
(Georgia Institute of Technology, 2007-02)
Bowen, Nathan J.; Logani, Sanjay; Dickerson, Erin B.; Kapa, Laura B.; Akhtar, Mariam; Benigno, Benedict B.; McDonald, John F.
Objectives.
Epithelial ovarian carcinomas develop from ovarian surface epithelia that undergo complex differentiation to form distinguishable
phenotypes resembling those of the epithelia of the female urogenital regions. While previous studies have implicated regulatory developmental
homeobox (HOX) genes in this process, other factors responsible for this differentiation are largely unknown. Aberrant transcriptional expression
of PAX8 has been reported in epithelial ovarian cancer, prompting us to initiate the molecular characterization of this master regulatory gene in
ovarian cancer development.
Methods.
Immunohistochemistry, immunoblotting and RT-PCR were used to investigate the presence of PAX8 and its protein products in
epithelial ovarian cancer subtypes, normal ovarian surface epithelia, ovarian inclusion cysts and normal endosalpingeal epithelia.
Results.
In this report, we confirm microarray results indicating that the transcription factor, PAX8, is highly expressed in epithelial ovarian
cancer but absent from the precursor ovarian surface epithelia of healthy individuals. Furthermore, we report that PAX8 is localized to the nucleus
of non-ciliated epithelia in simple ovarian epithelial inclusion cysts and in three epithelial ovarian cancer subtypes (serous, endometrioid and clear
cell). We also determined that PAX8 is expressed in the non-ciliated, secretory cells of healthy fallopian tube mucosal linings but not in the
adjacent ciliated epithelia.
Conclusion.
These findings support the hypothesis that PAX8 plays parallel roles in the development of epithelial ovarian cancer and in the
developmental differentiation of coelomic epithelia into endosalpingeal epithelia.