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

Lesterhuis WJ, Rinaldi C, Jones A, Rozali EN, Dick IM, Khong A, Boon L, Robinson BW, Nowak AK, Bosco A, Lake RA - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Treatment with CTLA4 blockade results in dichotomous and symmetric responses in identical tumor-bearing mice.(a) BALB/c mice were inoculated s.c. with AB1-HA mesothelioma cells on day 0, followed by i.p. injection of 200 μg anti-CTLA4 (n = 18) or PBS on day 6 or 7 (n = 21 mice, pooled data from 2 independent experiments). (b) Bilaterally inoculated AB1-HA tumor-bearing mice were treated with anti-CTLA4 on day 5 or 6 (n = 30 mice, pooled data from 2 independent experiments, colour-coded per mouse). Asymmetric responding tumours are marked with an asterisk. (c) Graphic representation of the experimental approach.
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f1: Treatment with CTLA4 blockade results in dichotomous and symmetric responses in identical tumor-bearing mice.(a) BALB/c mice were inoculated s.c. with AB1-HA mesothelioma cells on day 0, followed by i.p. injection of 200 μg anti-CTLA4 (n = 18) or PBS on day 6 or 7 (n = 21 mice, pooled data from 2 independent experiments). (b) Bilaterally inoculated AB1-HA tumor-bearing mice were treated with anti-CTLA4 on day 5 or 6 (n = 30 mice, pooled data from 2 independent experiments, colour-coded per mouse). Asymmetric responding tumours are marked with an asterisk. (c) Graphic representation of the experimental approach.

Mentions: In studies using anti-CTLA4 to treat mice with subcutaneous AB1-HA mesothelioma tumours12, we noticed that some of the mice did not respond while others displayed a rapid regression (Fig. 1a). Although this dichotomous response has been observed by many other groups before, both in mice131415 and in patients treated with anti-CTLA41, this finding struck us as surprising since the mice were genetically identical, experienced the same environment and were treated identically. In single tumour experiments, the outcome for an individual animal is only known at the end of the experiment, by which time the opportunity to study early events underlying regression has been lost. Therefore, we inoculated mice on both flanks with tumours, and observed that the treatment-induced response was symmetrical, in a highly reproducible manner over multiple experiments (Fig. 1b and Supplementary Table 1). Thus, this dual tumour model allowed detailed analysis of the early cellular and molecular events that occur in an anti-CTLA4 responsive tumour, without destroying the outcome readout (the remaining tumour), in the most informative setting: where responses are discordant between identically treated animals.


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

Lesterhuis WJ, Rinaldi C, Jones A, Rozali EN, Dick IM, Khong A, Boon L, Robinson BW, Nowak AK, Bosco A, Lake RA - Sci Rep (2015)

Treatment with CTLA4 blockade results in dichotomous and symmetric responses in identical tumor-bearing mice.(a) BALB/c mice were inoculated s.c. with AB1-HA mesothelioma cells on day 0, followed by i.p. injection of 200 μg anti-CTLA4 (n = 18) or PBS on day 6 or 7 (n = 21 mice, pooled data from 2 independent experiments). (b) Bilaterally inoculated AB1-HA tumor-bearing mice were treated with anti-CTLA4 on day 5 or 6 (n = 30 mice, pooled data from 2 independent experiments, colour-coded per mouse). Asymmetric responding tumours are marked with an asterisk. (c) Graphic representation of the experimental approach.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508665&req=5

f1: Treatment with CTLA4 blockade results in dichotomous and symmetric responses in identical tumor-bearing mice.(a) BALB/c mice were inoculated s.c. with AB1-HA mesothelioma cells on day 0, followed by i.p. injection of 200 μg anti-CTLA4 (n = 18) or PBS on day 6 or 7 (n = 21 mice, pooled data from 2 independent experiments). (b) Bilaterally inoculated AB1-HA tumor-bearing mice were treated with anti-CTLA4 on day 5 or 6 (n = 30 mice, pooled data from 2 independent experiments, colour-coded per mouse). Asymmetric responding tumours are marked with an asterisk. (c) Graphic representation of the experimental approach.
Mentions: In studies using anti-CTLA4 to treat mice with subcutaneous AB1-HA mesothelioma tumours12, we noticed that some of the mice did not respond while others displayed a rapid regression (Fig. 1a). Although this dichotomous response has been observed by many other groups before, both in mice131415 and in patients treated with anti-CTLA41, this finding struck us as surprising since the mice were genetically identical, experienced the same environment and were treated identically. In single tumour experiments, the outcome for an individual animal is only known at the end of the experiment, by which time the opportunity to study early events underlying regression has been lost. Therefore, we inoculated mice on both flanks with tumours, and observed that the treatment-induced response was symmetrical, in a highly reproducible manner over multiple experiments (Fig. 1b and Supplementary Table 1). Thus, this dual tumour model allowed detailed analysis of the early cellular and molecular events that occur in an anti-CTLA4 responsive tumour, without destroying the outcome readout (the remaining tumour), in the most informative setting: where responses are discordant between identically treated animals.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus