A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery.
The U.S. National Cancer Institute has used a panel of 60 diverse human cancer cell lines (the NCI-60) to screen >100,000 chemical compounds for anticancer activity. However, not all important cancer types are included in the panel, nor are drug responses of the panel predictive of clinical efficacy in patients. We asked, therefore, whether it would be possible to extrapolate from that rich database (or analogous ones from other drug screens) to predict activity in cell types not included or, for that matter, clinical responses in patients with tumors. We address that challenge by developing and applying an algorithm we term "coexpression extrapolation" (COXEN). COXEN uses expression microarray data as a Rosetta Stone for translating from drug activities in the NCI-60 to drug activities in any other cell panel or set of clinical tumors. Here, we show that COXEN can accurately predict drug sensitivity of bladder cancer cell lines and clinical responses of breast cancer patients treated with commonly used chemotherapeutic drugs. Furthermore, we used COXEN for in silico screening of 45,545 compounds and identify an agent with activity against human bladder cancer.
Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
Jae K
JK
Lee
Dmytro M
DM
Havaleshko
Hyungjun
H
Cho
John N
JN
Weinstein
Eric P
EP
Kaldjian
John
J
Karpovich
Andrew
A
Grimshaw
Dan
D
Theodorescu
D000465:Algorithms; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents