title: Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations.
abstract: Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Telethon Kids Institute, The University of Western Australia, 100 Roberts Road, Subiaco WA 6008, Australia.
authors.forename: Anya
authors.initials: A
authors.lastname: Jones
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Esdy N
authors.initials: EN
authors.lastname: Rozali
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Dick
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.affiliation: Bioceros, Yalelaan 46, 3584 CM Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Robinson
authors.affiliation: 1] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia [2] Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Ave, Nedlands WA 6009, Australia.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.affiliation: Telethon Kids Institute, The University of Western Australia, 100 Roberts Road, Subiaco WA 6008, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bosco
authors.affiliation: 1] National Centre for Asbestos Related Diseases [2] School of Medicine and Pharmacology, University of Western Australia, The Harry Perkins Institute of Medical Research, 5th Floor, QQ Block, 6 Verdun Street, Nedlands WA 6009, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology; D004338:Drug Combinations; D058492:Drug Repositioning; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D007167:Immunotherapy; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D008807:Mice, Inbred BALB C; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D004338:Drug Combinations