PDF file - 1060K, CCSB derived signaling networks for distinct breast cancer metastases (S1); Chemical structures of the candidate repositioned drugs and their parameters for the "Rule of Five." (S2); Western Immunoblot analysis of RET, FYN and the down-stream pathway proteins in indicated cell lines (S3); Relationship between the brain metastasis core signaling network and ER, PR, HER2 status in different breast tumor cohorts (S4); Evaluation of p-FYN and p-RET activation and tumor loci surrounding edema and vessels in the brain metastatis mouse models (S5); Pharmacokinetic study of Sunitinib and Dasatinib accumulated in brain of the xenograft models (S6); The three-dimensional cubes for the best subtrees in the survival analysis (S7).
ARTICLE 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. Cancer Res; 73(20); 6149–63. ©2013 AACR.
