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Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer
- Source :
- Frontiers in Genetics, Vol 10 (2019), Frontiers in Genetics
- Publication Year :
- 2019
- Publisher :
- FRONTIERS MEDIA SA, 2019.
-
Abstract
- Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.
- Subjects :
- 0301 basic medicine
Oncology
medicine.medical_specialty
lcsh:QH426-470
repurposing
Context (language use)
Disease
drug repositioning
basal subtype
Interactome
03 medical and health sciences
0302 clinical medicine
Breast cancer
breast cancer
TARGETS
Internal medicine
non-cancer therapeutics
REVEALS
medicine
Genetics
Genetics (clinical)
Original Research
business.industry
MOLECULAR PORTRAITS
personalized metabolic models
PROLIFERATION
Cancer
ENTROPY
medicine.disease
3. Good health
Drug repositioning
lcsh:Genetics
030104 developmental biology
Drug development
030220 oncology & carcinogenesis
Cardiovascular agent
Molecular Medicine
business
GENOMICS
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Frontiers in Genetics, Vol 10 (2019), Frontiers in Genetics
- Accession number :
- edsair.doi.dedup.....0925d5359dc28e6c5374d9139f0f5b82