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

Our plain-English summary of Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations, by W.J. Lesterhuis, C. Rinaldi, A. Jones, et al (Scientific Reports, 2015).

The study

• Authors: W.J. Lesterhuis, C. Rinaldi, A. Jones, E.N. Rozali, I.M. Dick, A. Khong, L. Boon, B.W. Robinson, A.K. Nowak, A. Bosco, R.A. Lake
• Journal: Scientific Reports
• Published: 2015;5:12298
• Cited by: 53 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice, not a study of people exposed to asbestos. The tumours came from a mouse mesothelioma cell line originally induced by asbestos. Mice with tumours under the skin were treated with an antibody that blocks CTLA4, a molecule that holds back the immune system. Some mice responded and others did not. Response was usually the same for tumours on both flanks; it differed in only 13% of mice. So the authors removed one tumour per mouse and compared gene activity in 10 responders, 10 non-responders and 10 control mice given PBS (a salt solution). They found 8 groups of linked genes. An immune-related group was more active and a cancer-related group less active in responders. Removing CD8 T cells abolished the response. Adding isosorbide dinitrate raised the cure rate from 10% to 80%. VX680, all-trans retinoic acid and meticrane also significantly improved treatment. Overall, 4 of 14 tested drugs did so. The authors concluded that such drugs can increase response rates to CTLA4 blockade. They noted they used a single mouse tumour model at a single time point, and that whether the results apply to patients remains to be established.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: gene expression (microarray) and network analysis of mouse tumours, followed by drug-combination experiments in mice
• Who was studied: BALB/c mice carrying AB1-HA mesothelioma tumours. The gene expression comparison used 3 groups of 10 mice each: responders, non-responders and PBS-treated controls.
• Exposure: No asbestos exposure was studied. Tumours were grown from an asbestos-induced mouse mesothelioma cell line (AB1-HA). Mice were treated with anti-CTLA4 antibody, alone or combined with other drugs (for example isosorbide dinitrate, VX680, all-trans retinoic acid, meticrane).
• Main results:
  • In mice with tumours on both flanks, the response to anti-CTLA4 was asymmetric in only 13% of mice.
  • Network analysis found 8 gene modules. Module 2 (immune module) was upregulated in responders and enriched for T cell genes.
  • Module 4 (cancer module) was downregulated in responders.
  • Depleting CD8 T cells completely abolished the response to anti-CTLA4.
  • Inhibiting NOS2 with L-NNA significantly decreased the effectiveness of anti-CTLA4.
  • Isosorbide dinitrate alone had no effect on tumour growth. Combined with anti-CTLA4, it raised the cure rate from 10% to 80%.
  • The AURKB inhibitor VX680 significantly increased treatment efficacy over anti-CTLA4 alone.
  • Giving VX-680 at the same time as anti-CTLA4 caused substantial toxicity, so the experiments were repeated with the two drugs given one after the other.
  • All-trans retinoic acid (ATRA) with anti-CTLA4 significantly enhanced efficacy, with long-term cures in most mice.
  • Meticrane, a thiazide diuretic, significantly enhanced the efficacy of anti-CTLA4.
  • Overall, 4 of 14 tested drugs showed a significant improvement over anti-CTLA4 alone, and 3 more showed a consistent trend.
• The authors' conclusion: The authors concluded that drugs known to modulate expression of genes in the response-associated modules can increase response rates to CTLA4 blockade.
• Limitations the authors state:
  • The study looked at a single time point, a mixed cell population and a single mouse tumour model.
  • It remains to be established whether the results apply to other cancers and to cancer patients.
  • The drug-matching database (cMap) was built from human non-mesothelioma cancer cell lines grown in the laboratory, while the gene data came from mice.
  • Dosing and scheduling of the repurposed drugs were not extensively optimized.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma.

Related studies

• In vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma — S. Martinotti, E. Ranzato, et al. (2011)
• Novel functional view of the crocidolite asbestos-treated A549 human lung epithelial transcriptome reveals an intricate network of pathways with opposing functions — J.M. Hevel, L.C. Olson-Buelow, et al. (2008)
• Is there a role for immunotherapy in malignant pleural mesothelioma? — A. Tartarone, R. Lerose, et al. (2018)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)
• Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma — V. Volta, E. Ranzato, et al. (2013)
• Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity — W.J. Lesterhuis, J. Salmons, et al. (2013)

Browse more research in Scientific Reports, or return to medical research.