Loading...
Please wait, while we are loading the content...
A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Jin, Guangxu Fu, Changhe Zhao Cui, Kemi Chang, Jenny X. Wong, Stephen T. C. |
| Copyright Year | 2012 |
| Abstract | Little research has been done to address the huge opportunities that may exist to reposition existing approved or generic drugs for alternate uses in cancer therapy. In addition, there has been little work on strategies to reposition experimental cancer agents for testing in alternate settings that could shorten their clinical development time. Progress in each area has lagged, in part, because of the lack of systematic methods to define drug off-target effects (OTE) that might affect important cancer cell signaling pathways. In this study, we addressed this critical gap by developing an OTE-based method to repurpose drugs for cancer therapeutics, based on transcriptional responses made in cells before and after drug treatment. Specifically, we defined a new network component called cancer-signaling bridges (CSB) and integrated it with a Bayesian factor regression model (BFRM) to form a new hybrid method termed CSB-BFRM. Proof-of-concept studies were conducted in breast and prostate cancer cells and in promyelocytic leukemia cells. In each system, CSB-BFRM analysis could accurately predict clinical responses to more than 90% of drugs approved by the U.S. Food and Drug Administration and more than 75% of experimental clinical drugs that were tested. Mechanistic investigation of OTEs for several high-ranking drug-dose pairs suggested repositioning opportunities for cancer therapy, based on the ability to enforce retinoblastoma-dependent repression of important E2F-dependent cell-cycle genes. Together, our findings establish new methods to identify opportunities for drug repositioning or to elucidate the mechanisms of action of repositioned drugs. |
| Starting Page | 33 |
| Ending Page | 44 |
| Page Count | 12 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/72/1.toc.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2011/12/20/0008-5472.CAN-11-2333.full.pdf |
| Alternate Webpage(s) | http://citeseerx.ist.psu.edu/viewdoc/download;jsessionid=5C24C7E3BC9CEB57BD839A34D2D12F56?doi=10.1.1.218.8111&rep=rep1&type=pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/72/1/33.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2011/11/21/0008-5472.CAN-11-2333.full.pdf |
| Alternate Webpage(s) | http://www.compbio.cmu.edu/Jclub/S12/Jin%20et%20al,%20Cancer%20Research%202011.pdf |
| PubMed reference number | 22108825v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-11-2333 |
| DOI | 10.1158/0008-5472.can-11-2333 |
| Journal | Cancer research |
| Volume Number | 72 |
| Issue Number | 1 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Drug Repositioning Drug Screening Assays, Antitumor ERCC6 gene Leukemia, B-Cell Prostatic Neoplasms Repositioning (procedure) Repression, Psychology Therapeutic brand of coal tar Transcription, Genetic cancer cell leukemia |
| Content Type | Text |
| Resource Type | Article |
