Using functional signatures to identify repositioned drugs for breast, myelogenous leukemia and prostate cancer.
Using functional signatures to identify repositioned drugs for breast, myelogenous leukemia and prostate cancer.
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DOI：
10.1371/journal.pcbi.1002347
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发表时间：
2012-02
影响因子：
4.3
通讯作者：
DeLisi C
中科院分区：
文献类型：
--
作者：
Shigemizu D;Hu Z;Hung JH;Huang CL;Wang Y;DeLisi C
The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine. The effective drug of a given disease is aimed to bring abnormal functions associated with disease back to the normal state. Using expression profile as the surrogate marker of the cellular function, we introduce a novel procedure to identify candidate therapeutics by searching for those bioactive compounds that either down-regulate abnormally over-expressed genes, or up-regulate those that are abnormally under-expressed. We show that the approach detects a pool of plausible candidates as repositioning/new drugs. In contrast to previous studies, our approach uses a variable big number of genes and/or gene combinations as a representation of functional signatures to identify bioactive compounds that modulate a given disease, irrespective of the particular genes that contribute to the cellular functions; therefore it covers potential drugs with heterogeneous properties. The method may also have potential application for the personalized medicine.
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DOI：
10.1186/bcr2572
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Alvarez RH
通讯作者：
Alvarez RH
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
56.9
作者：
Campillos, Monica;Kuhn, Michael;Bork, Peer
通讯作者：
Bork, Peer
影响因子：
3.7
作者：
Belin S;Beghin A;Solano-Gonzàlez E;Bezin L;Brunet-Manquat S;Textoris J;Prats AC;Mertani HC;Dumontet C;Diaz JJ
通讯作者：
Diaz JJ
影响因子：
14.9
作者：
Hu Z;Hung JH;Wang Y;Chang YC;Huang CL;Huyck M;DeLisi C
通讯作者：
DeLisi C