Utility of network integrity methods in therapeutic target identification.

Analysis of the biological gene networks involved in a disease may lead to the identification of therapeutic targets. Such analysis requires exploring network properties, in particular the importance of individual network nodes (i.e., genes). There are many measures that consider the importance of nodes in a network and some may shed light on the biological significance and potential optimality of a gene or set of genes as therapeutic targets. This has been shown to be the case in cancer therapy. A dilemma exists, however, in finding the best therapeutic targets based on network analysis since the optimal targets should be nodes that are highly influential in, but not toxic to, the functioning of the entire network. In addition, cancer therapeutics targeting a single gene often result in relapse since compensatory, feedback and redundancy loops in the network may offset the activity associated with the targeted gene. Thus, multiple genes reflecting parallel functional cascades in a network should be targeted simultaneously, but require the identification of such targets. We propose a methodology that exploits centrality statistics characterizing the importance of nodes within a gene network that is constructed from the gene expression patterns in that network. We consider centrality measures based on both graph theory and spectral graph theory. We also consider the origins of a network topology, and show how different available representations yield different node importance results. We apply our techniques to tumor gene expression data and suggest that the identification of optimal therapeutic targets involving particular genes, pathways and sub-networks based on an analysis of the nodes in that network is possible and can facilitate individualized cancer treatments. The proposed methods also have the potential to identify candidate cancer therapeutic targets that are not thought to be oncogenes but nonetheless play important roles in the functioning of a cancer-related network or pathway.