Differential prioritization of therapies to subtypes of triple negative breast cancer using a systems medicine method.

Content Provider	Europe PMC
Author	Wathieu, Henri Issa, Naiem T. Fernandez, Aileen I. Mohandoss, Manisha Tiek, Deanna M. Franke, Jennifer L. Byers, Stephen W. Riggins, Rebecca B. Dakshanamurthy, Sivanesan
Copyright Year	2017
Abstract	Triple negative breast cancer (TNBC) is a group of cancers whose heterogeneity and shortage of effective drug therapies has prompted efforts to divide these cancers into molecular subtypes. Our computational platform, entitled GenEx-TNBC, applies concepts in systems biology and polypharmacology to prioritize thousands of approved and experimental drugs for therapeutic potential against each molecular subtype of TNBC. Using patient-based and cell line-based gene expression data, we constructed networks to describe the biological perturbation associated with each TNBC subtype at multiple levels of biological action. These networks were analyzed for statistical coincidence with drug action networks stemming from known drug-protein targets, while accounting for the direction of disease modulation for coinciding entities. GenEx-TNBC successfully designated drugs, and drug classes, that were previously shown to be broadly effective or subtype-specific against TNBC, as well as novel agents. We further performed biological validation of the platform by testing the relative sensitivities of three cell lines, representing three distinct TNBC subtypes, to several small molecules according to the degree of predicted biological coincidence with each subtype. GenEx-TNBC is the first computational platform to associate drugs to diseases based on inverse relationships with multi-scale disease mechanisms mapped from global gene expression of a disease. This method may be useful for directing current efforts in preclinical drug development surrounding TNBC, and may offer insights into the targetable mechanisms of each TNBC subtype.
Journal	Oncotarget
Volume Number	8
PubMed Central reference number	PMC5696233
Issue Number	54
PubMed reference number	29190967
e-ISSN	19492553
DOI	10.18632/oncotarget.21669
Language	English
Publisher	Impact Journals LLC
Publisher Date	2017-10-09
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. Copyright: © 2017 Wathieu et al.
Subject Keyword	triple negative breast cancer systems biology gene expression analysis molecular subtyping drug development
Content Type	Text
Resource Type	Article
Subject	Oncology