Abstract 2906: Towards breast cancer drug repurposing based on a pathway modeling approach.
Sara Ibrahim · Cancer Research · 2013
Abstract Molecular connectivity maps between drugs and proteins in specific disease contexts, especially breast cancer, can be particularly valuable, offering an opportunity to gain global perspectives on both the therapeutic and toxicological profiles of drugs. To assess drug pharmacological effects, we assume that “ideal” drugs for a patient can treat or prevent disease by modulating gene expression profiles of the patient to the similar level with those in healthy people. Starting from this hypothesis, we build comprehensive disease-gene-drug connectivity relationships with drug-protein directionality (inhibit/activate) information based on a computational connectivity maps (CMaps) platform. In this work, we develop a novel approach based on integrative pathway modeling using breast cancer as a case study. We identify and rank breast cancer related drugs/compounds with their overall drug-protein “connectivity map” profile. First, we retrieve breast cancer associated proteins through the CMaps platform by using breast cancer as a query term. Second, we retrieve breast cancer related pathways by using breast cancer associated proteins as input and searching in the Human Pathway Database (HPD), PAGED, and the PubMed. Third, we integrate the breast cancer related pathways into unified pathway models, from which we categorize the pharmaceutical effects of candidate drugs on all breast cancer associated proteins as either “therapeutic” or “toxic”. Expression values are given to all relevant proteins on the pathway. Potential drugs and targets are retrieved from C-Map, DrugBank, and MetaDrug. Finally, we transform the integrated pathway into network models and rank drugs based on the network topological features of drug targets, drug-affecting genes/proteins, and curated disease-associated proteins. The case studies correlated very well with the known pharmacological profiles of cancer drugs, highlighting the significance of the platform that we developed. Ongoing research can potentially change future drug discovery practices. Citation Format: Sara Ibrahim. Towards breast cancer drug repurposing based on a pathway modeling approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2906. doi:10.1158/1538-7445.AM2013-2906