A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer

PLoS One. 2016 Sep 15;11(9):e0162407. doi: 10.1371/journal.pone.0162407. eCollection 2016.

Abstract

The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our "in-silico" findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing.

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Female
  • Humans
  • Models, Theoretical
  • Monte Carlo Method
  • Systems Integration*
  • Triple Negative Breast Neoplasms / drug therapy*

Substances

  • Antineoplastic Agents

Grants and funding

This work was supported by Regione Lombardia through the project "Metodologie e tecnologie bioinformatiche per l'integrazione di informazioni cliniche e conscenze biologiche a supporto della ricerca translazionale in oncologia (Onco-i2b2)"- A1.2010.0103195—http://www.regione.lombardia.it/. The in vitro experiments were conducted through the support of Associazione Italiana per la Ricerca sul Cancro AIRC 5x1000 Program (2010–2015) Grant (10016-http://www.airc.it/aiutare-la-ricerca/5-per-mille.asp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.