(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, 2007-05-17)
Moreno, Carlos S.; Matyunina, Lilya V.; Dickerson, Erin B.; Schubert, Nina; Bowen, Nathan J.; Logani, Sanjay; Benigno, Benedict B.; McDonald, John F.
Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-treated with chemotherapy
(neo-adjuvant) prior to surgery group into two distinct clusters. One group clusters with carcinomas from patients not pretreated
with chemotherapy prior to surgery (C-L), while the other clusters with non-malignant adenomas (A-L). We show here
that although the C-L cluster is preferentially associated with p53 loss-of-function (LOF) mutations, the C-L cluster cancer
patients display a more favorable clinical response to chemotherapy as evidenced by enhanced long-term survivorships. Our
results support a model whereby p53 mediated cell-cycle-arrest/DNA repair serves as a barrier to optimal chemotherapeutic
treatment of ovarian and perhaps other carcinomas and suggest that inhibition of p53 during chemotherapy may enhance
clinical outcome.
(Georgia Institute of Technology, 2007-01-25)
Menendez, Laura; Walker, L. DeEtte; Matyunina, Lilya V.; Dickerson, Erin B.; Bowen, Nathan J.; Benigno, Benedict B.; McDonald, John F.
Background: Aberrant methylation of gene promoter regions has been linked to changes in gene
expression in cancer development and progression. Genes associated with CpG islands (CGIs) are
especially prone to methylation, but not all CGI-associated genes display changes in methylation
patterns in cancers.
Results: In order to identify genes subject to regulation by methylation, we conducted gene
expression profile analyses of an ovarian cancer cell line (OVCAR-3) before and after treatment
with the demethylating agent 5-aza-deoxycytidine (5-aza-dC). An overlapping subset of these genes
was found to display significant differences in gene expression between normal ovarian surface
epithelial cells and malignant cells isolated from ovarian carcinomas. While 40% of all human genes
are associated with CGIs, > 94% of the overlapping subset of genes is associated with CGIs. The
predicted change in methylation status of genes randomly selected from the overlapping subset was
experimentally verified.
Conclusion: We conclude that correlating genes that are upregulated in response to 5-aza-dC
treatment of cancer cell lines with genes that are down-regulated in cancer cells may be a useful
method to identify genes experiencing epigenetic-mediated changes in expression over cancer
development.