Identification of novel drug targets through a systems approach

To develop a complete understanding of a complex disease, such as cancer and auto-immune diseases, information must cover multiple dimensions. Over the last few years, we have witnessed decisive advances in bioinformatics, genome sequencing, and high-throughput technologies that have highlighted the need for approaching complex diseases as a whole. Today, our ability to analyze the entire set of genes (genome), epigenetic modifications (epigenome), transcriptional regulation (transcriptome), protein interactions (proteome) and the identification of novel algorithms and software able to integrate all the ‘omics’ data, enabled the genesis of the systems biology field. Our group was one of the first to apply a systems biology approach by integrating different “omics” data by the use of Paradigm and Ingenuity algorithms, aiming to identify the central regulators of disease networks. Furthermore, the identification of disease molecular networks has allowed us to identify novel drugs targeting these networks following an approach that we have developed in our Center for Systems Biomedicine at UCLA, named “Network-based Chemical Screening” (NCS). We have successfully identified novel therapeutic targets for different diseases, including cancer, pulmonary diseases, lupus and osteoarthritis by applying a systems biology approach, suggesting the wide applicability and effectiveness of this approach.

A. Hirsch HA*, Iliopoulos D*, Joshi A*, Zhang Y, Jaeger SA, Bulyk M, Liu SX, Struhl K. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 17: 348-61, 2010. *equal contribution

The findings of this study were featured in “The Scientist” magazine (article by Megan Scudellari on April 12th, 2010). This article was presented in the Focus Magazine (April 23, 2010) and websites of Harvard Medical School, Dental School and School of Public Health. Evaluated as an “exceptional” paper by Faculty of 1000 Biology. This article was presented in Nature Reviews Genetics (11:386, 2010) and Nature Reviews Cancer (10:387, 2010).

B. Nakou M, Bertsias G, Stagakis I, Centola M, Tassiulas I, Hatziapostolou M, Kritikos I, Goulielmos G, Boumpas DT, Iliopoulos D. Gene network analysis of bone marrow mononuclear cells reveals activation of multiple kinase pathways in human systemic lupus erythematosus. PLoS One 2010; 5:e13351.

C. Vaporidi K, Vergadi E, Kaniaris E, Hatziapostolou M, Lagoudaki E, Georgopoulos D, Zapol WM, Bloch KD, Iliopoulos D. Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2012; 303:L199-207.

D. Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y, Mai J, Shen H, Hu DZ, Adoro S, Hu B, Song M, Landis MD, Ferrari M, Shin SJ, Brown M, Chang JC, Liu XS, Glimcher LH. XBP1 promotes triple-negative breast cancer by controlling the HIF1a pathway. Nature 2014 508:103-7. PMCID: PMC4105133