Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers.
Journal Article (Journal Article)
Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High-grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore, discovery of efficacious new drugs in this setting is required to benefit chemorefractory cases. The 50% growth-inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug and then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemorefractory cases. Using these candidates, cell proliferation, apoptosis and caspase assays were performed in vitro. The tumor growth-inhibitory effect of the candidate was also assessed in vivo using nude mice. Through microarray analysis, fludarabine and temsirolimus showed higher susceptibility scores in high-grade cases compared to cisplatin, doxorubicin and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p < 0.001). Fludarabine treatment also enhanced caspase-3/7 activity in HEC1A relative to HEC50B cells (p < 0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p < 0.05). These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemoresistant cases. Fludarabine may be useful in targeting high-grade, chemorefractory endometrial cancer.
Full Text
Duke Authors
Cited Authors
- Kharma, B; Baba, T; Mandai, M; Matsumura, N; Murphy, SK; Kang, HS; Yamanoi, K; Hamanishi, J; Yamaguchi, K; Yoshioka, Y; Konishi, I
Published Date
- November 2013
Published In
Volume / Issue
- 133 / 9
Start / End Page
- 2234 - 2244
PubMed ID
- 23595697
Electronic International Standard Serial Number (EISSN)
- 1097-0215
Digital Object Identifier (DOI)
- 10.1002/ijc.28220
Language
- eng
Conference Location
- United States