Genetic Network Analysis to Identify Synergistic Drug-Immunotherapy Combinations

University of Western Australia Background
Most patients do not respond to cancer immunotherapy and it is not known what molecular events differentiate those who respond, from those that do not. By visualising responses to immunotherapy as a network of interacting gene products, it is possible to predict effective drug interventions.
Technology Overview
Researchers at the University of Western Australia (UWA) have used a mouse mesothelioma model that displays a dichotomous response to anti-CTLA4 treatment, as a model to identify clusters of candidate gene networks (or ‘modules’), associated with ‘responder’ and ‘progresser’ animals. Identification of these modules was performed via a network analysis approach (), correlating gene expression analysis with the response to immunotherapy.
The mouse mesothelioma model shows a symmetrical response in bilateral tumours, with tumours on each flank either responding or progressing. This creates an opportunity to study immunotherapy induced regressing cancer, and to identify early events underlying/driving responses.
In the example mesothelioma mouse model, anti-CTL4A treatment resulted in the upregulation of certain ‘immune modules’ in responder animals, including an enrichment of genes involved in cell cycle control.
Identified modules were then targeted by drugging central ‘hub’ genes, such as nitric oxide synthase (NOS), which has been identified as highly upregulated in responder animals. To highlight the utility of UWA’s network analysis approach in identifying this crucial ‘immune module’, the combination of a Nitrogen Oxide (NO) generator (called ISDN) in combination with anti-CTLA4 treatment, increased survival rates from 10% to 80% in mice ().
Applications
Repurposing drugs (ISDN is an approved drug developed for CV disease):

Repurposing of known, approved drugs
Repositioning/resurrection of in-house CPDs shelved for failed efficacy

Defining new context-specific (combination drug) targets.Platform potential:

In a second context (instead of looking at response vs non-response) looking at invasive vs non-invasive cancers, team have identified a novel target and repurposed cpds for mesothelioma

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