I. Ramirez

The Role of Surgery in the Management of Epithelial Ovarian Cancer

BACKGROUND Epithelial ovarian cancer is the most deadly gynecologic cancer in the United States. Multiple modalities of therapy are utilized in the management of the disease. The role of surgery remains important in the treatment of this disease and is described herein. METHODS Medline and PubMed were utilized to search the English language medical literature up to March 2010. A broad range of studies and quality of data were analyzed, including prospective studies, case control analyses, and meta-analyses. When possible, the highest level of evidence was reviewed and presented. RESULTS For the medically fit patient, optimal cytoreductive surgery positively impacts survival. For some highly selected patients, there is a role for a minimally invasive approach. In the recurrent setting, factors such as interval to recurrence and the distribution of disease will determine the utility of secondary cytoreductive surgery. A subgroup of patients may benefit from palliative surgical procedures in the recurrent setting. CONCLUSIONS Despite advances in the use of chemotherapy and biologic agents, surgery remains an important modality in the diagnosis and treatment of ovarian cancer.

Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance

OBJECTIVES Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy. METHODS In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes. RESULTS Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA. CONCLUSIONS Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA.

Perifosine, an AKT inhibitor, modulates ovarian cancer cell line sensitivity to cisplatin-induced growth arrest

OBJECTIVES AKT, a key regulator of diverse tumor signaling, is associated with progression of many cancers. Here, we investigated 1) the influence of AKT on survival from ovarian cancer (OVCA), 2) the activity of the AKT inhibitor perifosine ± cisplatin, and 3) the molecular determinants of perifosine-response. Phospho-AKT expression values and Affymetrix U133a expression data were downloaded from The Cancer Genome Atlas. METHODS Pearson correlation was used to determine associations between overall survival from OVCA and therapy response. Genes and represented signaling pathways associated with perifosine-response were explored in OVCA cells (n=10) and the NCI60 cancer cell panel. Pathway expressions, modeled by PCA, were evaluated for influences on survival using publically available clinico-genomic datasets. RESULTS Phospho-AKT (serine473) expression correlated with survival from OVCA (P<0.05) and platinum-response (P=0.004). In vitro, perifosine showed anti-proliferative effects against OVCA cells and potentiated cisplatin-induced growth arrest. Perifosine-response was associated with the expression (FDR<0.05) of 7 signaling pathways in OVCA cells and 64 signaling pathways in the NCI60 cell panel. Three pathways were found in common: 1) Cytoskeleton remodeling/cytoskeleton remodeling (cyto), 2) cell adhesion/chemokines and adhesion (chemokines), and 3) cytoskeleton remodeling/TGF-WNT (TGF-WNT). The TGF-WNT was associated with survival from OVCA (P=0.0055). CONCLUSIONS AKT signaling is an important determinant of OVCA response to chemotherapy and overall patient survival. Our data provide insight into the molecular basis to perifosine activity and identifies pathways associated with perifosine sensitivity and patient clinical outcome.