title: Prediction of drug combination chemosensitivity in human bladder cancer.
abstract: The choice of therapy for metastatic cancer is largely empirical because of a lack of chemosensitivity prediction for available combination chemotherapeutic regimens. Here, we identify molecular models of bladder carcinoma chemosensitivity based on gene expression for three widely used chemotherapeutic agents: cisplatin, paclitaxel, and gemcitabine. We measured the growth inhibition elicited by these three agents in a series of 40 human urothelial cancer cell lines and correlated the GI(50) (50% of growth inhibition) values with quantitative measures of global gene expression to derive models of chemosensitivity using a misclassification-penalized posterior approach. The misclassification-penalized posterior-derived models predicted the growth response of human bladder cancer cell lines to each of the three agents with sensitivities of between 0.93 and 0.96. We then developed an in silico approach to predict the cellular growth responses for each of these agents in the clinically relevant two-agent combinations. These predictions were prospectively evaluated on a series of 15 randomly chosen bladder carcinoma cell lines. Overall, 80% of the predicted combinations were correct (P = 0.0002). Together, our results suggest that chemosensitivity to drug combinations can be predicted based on molecular models and provide the framework for evaluation of such models in patients undergoing combination chemotherapy for cancer. If validated in vivo, such predictive models have the potential to guide therapeutic choice at the level of an individual's tumor.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Box 422, Charlottesville, VA 22908, USA.
authors.forename: Dmytro M
authors.initials: DM
authors.lastname: Havaleshko
authors.forename: HyungJun
authors.initials: H
authors.lastname: Cho
authors.forename: Mark
authors.initials: M
authors.lastname: Conaway
authors.forename: Charles R
authors.initials: CR
authors.lastname: Owens
authors.forename: Garret
authors.initials: G
authors.lastname: Hampton
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine