Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations

被引：57

作者：

Lesterhuis, W. Joost ^{[1
,2
]}

Rinaldi, Catherine ^{[1
,2
]}

Jones, Anya ^{[3
]}

Rozali, Esdy N. ^{[1
,2
]}

Dick, Ian M. ^{[1
,2
]}

Khong, Andrea ^{[1
,2
]}

Boon, Louis ^{[4
]}

Robinson, Bruce W. ^{[1
,2
]}

Nowak, Anna K. ^{[2
,5
]}

Bosco, Anthony ^{[3
]}

Lake, Richard A. ^{[1
,2
]}

机构：

[1] Univ Western Australia, Harry Perkins Inst Med Res, Natl Ctr Asbestos Related Diseases, Nedlands, WA 6009, Australia

[2] Univ Western Australia, Harry Perkins Inst Med Res, Sch Med & Pharmacol, Nedlands, WA 6009, Australia

[3] Univ Western Australia, Telethon Kids Inst, Subiaco, WA 6008, Australia

[4] Bioceros, NL-3584 CM Utrecht, Netherlands

[5] Sir Charles Gairdner Hosp, Dept Med Oncol, Nedlands, WA 6009, Australia

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

基金：

英国医学研究理事会;

关键词：

ANTIGEN-4; BLOCKADE; KINASE INHIBITOR; RETINOIC ACID; IN-VIVO; CANCER; RESPONSES; CELLS; INFLAMMATION; PROGRESSION; IPILIMUMAB;

D O I：

10.1038/srep12298

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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