Utilization of genomic signatures to identify high‐efficacy candidate drugs for chemorefractory endometrial cancers

• Published in: International journal of cancer 2013-11, Vol.133 (9), p.2234-2244
• Main Authors: Kharma, Budiman, Baba, Tsukasa, Mandai, Masaki, Matsumura, Noriomi, Murphy, Susan K., Kang, Hyun Sook, Yamanoi, Koji, Hamanishi, Junzo, Yamaguchi, Ken, Yoshioka, Yumiko, Konishi, Ikuo
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Bayes Theorem; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer; Cancer therapies; Carboplatin - administration & dosage; Cell growth; Cell Proliferation - drug effects; chemodynamics; chemoresistant; Chemotherapy; Cisplatin - administration & dosage; Doxorubicin - administration & dosage; Drug Resistance, Neoplasm - genetics; Endometrial cancer; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Female; fludarabine; Follow-Up Studies; Gene expression; Gene Expression Profiling - utilization; Genomics; Humans; Medical research; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Grading; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Paclitaxel - administration & dosage; Pharmacology. Drug treatments; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Survival Rate; Tumor Cells, Cultured; Tumors; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28220

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. What's new? Patients with advanced endometrial cancer need something beyond conventional therapies. Genome wide microarray analysis of these difficult‐to‐treat cancers has shown that they have distinctive genetic signatures. In this paper, the authors profiled drug‐resistant endometrial cancer cell lines to identify potentially effective chemical therapies. From their analysis, they determined that that five of seven cancer cell lines were likely susceptible to the chemotherapy agent fludarabine. They then demonstrated fludarabine's toxicity in vitro and in vivo, suggesting the drug may have promise for treating the cancer.