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Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Zhao, Huiying Jin, Guangxu Cui, Kemi Ren, Ding Liu, Timothy James Chen, Peikai Wong, Solomon Li, Fuhai Fan, Yubo Rodríguez, Angel Cuza Chang, Jenny X. Wong, Stephen T. C. |
| Copyright Year | 2013 |
| Abstract | A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. |
| Starting Page | 977 |
| Ending Page | 978 |
| Page Count | 2 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/73/20/6149.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2013/10/04/0008-5472.CAN-12-4617.full.pdf |
| PubMed reference number | 24097821v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-12-4617 |
| DOI | 10.1158/0008-5472.can-12-4617 |
| Journal | Cancer research |
| Volume Number | 73 |
| Issue Number | 20 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Drug Screening Assays, Antitumor Gene Expression Mammary Neoplasms Metastatic malignant neoplasm to brain Neoplasm Metastasis New type Patients Repositioning (procedure) Specimen Structure of parenchyma of lung Substance Abuse Detection Subtype (attribute) bone metastases cancer cell dasatinib sunitinib |
| Content Type | Text |
| Resource Type | Article |
