title: Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers.
abstract: 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.
authors.affiliation: Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Budiman
authors.initials: B
authors.lastname: Kharma
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Baba
authors.forename: Masaki
authors.initials: M
authors.lastname: Mandai
authors.forename: Noriomi
authors.initials: N
authors.lastname: Matsumura
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Kang
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanoi
authors.forename: Junzo
authors.initials: J
authors.lastname: Hamanishi
authors.forename: Ken
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Ikuo
authors.initials: I
authors.lastname: Konishi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000706:statistics & numerical data*; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C401859:temsirolimus; D004317:Doxorubicin; D016190:Carboplatin; D014740:Vidarabine; C024352:fludarabine; D017239:Paclitaxel; D002945:Cisplatin; D020123:Sirolimus
keywords: chemodynamics; chemoresistant; endometrial cancer; fludarabine