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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

Repurposed drugs that phenocopy the gene expression profile of response-associated modules synergize with anti-CTLA4.Survival curve of AB1-HA tumour-bearing mice treated with anti-CTLA4 in combination with (a) ATRA and (b) meticrane improved therapeutic efficacy of anti-CTLA4. Representative survival curves of 3 independent experiments are shown, n = 10 mice per arm; *p < 0.05; **p < 0.01.
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f5: Repurposed drugs that phenocopy the gene expression profile of response-associated modules synergize with anti-CTLA4.Survival curve of AB1-HA tumour-bearing mice treated with anti-CTLA4 in combination with (a) ATRA and (b) meticrane improved therapeutic efficacy of anti-CTLA4. Representative survival curves of 3 independent experiments are shown, n = 10 mice per arm; *p < 0.05; **p < 0.01.

Mentions: Given that selective drugs are often not available to target hub genes, we wanted to explore an alternative and more generalized approach to find drugs that can increase therapeutic efficacy. To address this issue, we hypothesized that repurposed drugs that modulate expression levels of multiple genes within the response modules may also improve treatment response. Two different computational tools were employed for this analysis. The first approach utilized the connectivity map (cMap) database2122, which contains genome-wide expression signatures of cell lines induced by 1309 compounds22 (Supplementary Table 4). The second approach utilized upstream regulator analysis23, which identifies drugs that are known a priori to modulate the expression levels of genes that are differentially expressed in a data set, and additionally measures the pattern match between the observed expression changes (up/down regulation) and the predicted pattern from prior knowledge (Supplementary Table 5). In both analyses retinoic acid was identified as a potential candidate. Retinoic acid exerts differential effects on immune cells, including effector T cells, macrophages, dendritic cells and suppressive cell subsets242526. All-trans retinoic acid (ATRA) is used in acne skin disease and in promyelocytic leukemia as stem cell differentiation inducer, but it has never been used in combination with checkpoint blockade before. In vivo validation experiments showed a significant enhancement of treatment efficacy when ATRA was co-administered with CTLA-4 blockade, with long-term cures in the majority of mice (Fig. 5a). In addition, we tested multiple other drugs based on the ranking within the cMap analysis and availability. Meticrane, a thiazide diuretic was highly ranked in the cMap analysis, and it does not have any known anti-cancer or immune-stimulating effect. Co-treatment with meticrane significantly enhanced treatment efficacy of CTLA-4 blockade (Fig. 5b).


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)

Repurposed drugs that phenocopy the gene expression profile of response-associated modules synergize with anti-CTLA4.Survival curve of AB1-HA tumour-bearing mice treated with anti-CTLA4 in combination with (a) ATRA and (b) meticrane improved therapeutic efficacy of anti-CTLA4. Representative survival curves of 3 independent experiments are shown, n = 10 mice per arm; *p < 0.05; **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Repurposed drugs that phenocopy the gene expression profile of response-associated modules synergize with anti-CTLA4.Survival curve of AB1-HA tumour-bearing mice treated with anti-CTLA4 in combination with (a) ATRA and (b) meticrane improved therapeutic efficacy of anti-CTLA4. Representative survival curves of 3 independent experiments are shown, n = 10 mice per arm; *p < 0.05; **p < 0.01.
Mentions: Given that selective drugs are often not available to target hub genes, we wanted to explore an alternative and more generalized approach to find drugs that can increase therapeutic efficacy. To address this issue, we hypothesized that repurposed drugs that modulate expression levels of multiple genes within the response modules may also improve treatment response. Two different computational tools were employed for this analysis. The first approach utilized the connectivity map (cMap) database2122, which contains genome-wide expression signatures of cell lines induced by 1309 compounds22 (Supplementary Table 4). The second approach utilized upstream regulator analysis23, which identifies drugs that are known a priori to modulate the expression levels of genes that are differentially expressed in a data set, and additionally measures the pattern match between the observed expression changes (up/down regulation) and the predicted pattern from prior knowledge (Supplementary Table 5). In both analyses retinoic acid was identified as a potential candidate. Retinoic acid exerts differential effects on immune cells, including effector T cells, macrophages, dendritic cells and suppressive cell subsets242526. All-trans retinoic acid (ATRA) is used in acne skin disease and in promyelocytic leukemia as stem cell differentiation inducer, but it has never been used in combination with checkpoint blockade before. In vivo validation experiments showed a significant enhancement of treatment efficacy when ATRA was co-administered with CTLA-4 blockade, with long-term cures in the majority of mice (Fig. 5a). In addition, we tested multiple other drugs based on the ranking within the cMap analysis and availability. Meticrane, a thiazide diuretic was highly ranked in the cMap analysis, and it does not have any known anti-cancer or immune-stimulating effect. Co-treatment with meticrane significantly enhanced treatment efficacy of CTLA-4 blockade (Fig. 5b).

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