In silico transcriptomics identifies FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss
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Curated by eLife
Evaluation Summary:
In this report, the authors have combined analysis of the Connectivity Map with small molecule screens in zebrafish to identify compounds that may spare ototoxicity induced from cisplatin. This is an important limitation of this effective and widely used chemotherapeutic agent and has the potential to create approaches to limit the neurotoxicity induced by cisplatin.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
Acquired hearing loss is a major health problem that affects 5-10% of the world population. However, there are no FDA-approved drugs for the treatment or prevention of hearing loss. Employing the Connectivity Map (CMap) that contains >54,000 compounds, we performed an unbiased in silico screen using the transcriptomic profiles of cisplatin-resistant and -sensitive cancer cell lines. Pathway enrichment analysis identified gene-drug targets for which 30 candidate drugs were selected with potential to confer protection against cisplatin-induced ototoxicity. In parallel, transcriptomic analysis of a cisplatin-treated cochlear-derived cell line identified common enriched pathway targets. We subsequently tested these top 30 candidate compounds, 15 (50%) of which are FDA-approved for other indications, and 26 (87%) of which were validated for their protective effects in either a cochlear-derived cell line or zebrafish lateral line neuromasts, thus confirming our in silico transcriptomic approach. Among these top compounds, niclosamide, a salicyanilide drug approved by the FDA for treating tapeworm infections for decades, protected from cisplatin- and noise-induced hearing loss in mice. Finally, niclosamide and ezetimibe (an Nrf2 agonist) exerted synergistic protection against cisplatin-ototoxicity in zebrafish, validating the Nrf2 pathway as part of niclosamide’s mechanism of action. Taken together, employing the CMap, we identified multiple pathways and drugs against cisplatin ototoxicity and confirmed that niclosamide can effectively be repurposed as an otoprotectant for future clinical trials against cisplatin- and noise-induced hearing loss.
Significant Statement
Employing the Connectivity Map as our in silico transcriptomic screening strategy we identified FDA-approved drugs and biological pathways for protection against cisplatin-induced hearing loss.
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Evaluation Summary:
In this report, the authors have combined analysis of the Connectivity Map with small molecule screens in zebrafish to identify compounds that may spare ototoxicity induced from cisplatin. This is an important limitation of this effective and widely used chemotherapeutic agent and has the potential to create approaches to limit the neurotoxicity induced by cisplatin.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
This manuscript describes a clever strategy to nominate existing drugs for testing for their ability to abrogate the well-known negative effects of platinum-containing chemotherapeutic drugs on hearing. This is an important clinical problem, and as such if existing drugs actually had the ability to mitigate hearing loss when given in combination with cisplatin (assuming the combination is well-tolerated and the combination does not mitigate the anti-cancer effects of cisplatin), the potential for clinical impact would be substantial.
The authors first define a gene expression signature of cisplatin resistance, using publicly available gene expression datasets of cell lines that are either sensitive (meaning are killed by) to cisplatin, or are resistant to it. They then use that signature of resistance to …
Reviewer #1 (Public Review):
This manuscript describes a clever strategy to nominate existing drugs for testing for their ability to abrogate the well-known negative effects of platinum-containing chemotherapeutic drugs on hearing. This is an important clinical problem, and as such if existing drugs actually had the ability to mitigate hearing loss when given in combination with cisplatin (assuming the combination is well-tolerated and the combination does not mitigate the anti-cancer effects of cisplatin), the potential for clinical impact would be substantial.
The authors first define a gene expression signature of cisplatin resistance, using publicly available gene expression datasets of cell lines that are either sensitive (meaning are killed by) to cisplatin, or are resistant to it. They then use that signature of resistance to query the Connectivity Map, which is a publicly accessible database of gene expression profiles following genetic and small molecule perturbation. The authors thus aimed to find drugs that phenocopy the cisplatin-resistance signature.
This analysis yielded a large number of candidate drugs, which was whittled down to a smaller number (30) based on a number of bioinformatic analyses. These top candidates were then tested in cellular and animal (zebrafish and mouse) models of cisplatin-induced hearing loss, and found that the vast majority (87%) showed some evidence of hearing protection in at least one of the in vivo models, and half of the top compounds scored in both in vivo assays. The FDA-approved drug niclosamide was explored in greater detail.
The strengths of the study include a) its tackling of a clinically important problem, b) its clever use of the Connectivity Map for discovery, and c) the validation of top compounds in what appear to be relevant in vivo models of cisplatin-induced hearing loss.
The weaknesses of the study include a) the lack of any mechanistic insights into how niclosamide and other top scoring compounds are acting, and b) the lack of a thorough testing of niclosamide's lack of an ability to cause cisplatin resistance with respect to cisplatin's anti-cancer activity.
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Reviewer #2 (Public Review):
This study performed in silico screens on Connectivity Map (CMap) to identify transcriptomic profiles of cisplatin-resistant and cisplatin-sensitive cancer cell lines for the purpose of identifying and repurposing FDA-approved compounds as potential otoprotectants against cisplatin-induced hearing loss. Niclosamide, an FDA-approved drug for tapeworm treatment with a favorable safety profile, was identified through this screening method and validated using mice and zebrafish, demonstrating protective effects against cisplatin- and noise-induced hair cell loss and partial protection from hearing loss.
The premise of using transcriptomic profiles of cancer cell lines to model the profiles of inner ear hair cells in response to FDA-approved compounds has not previously been explored and provides a novel …
Reviewer #2 (Public Review):
This study performed in silico screens on Connectivity Map (CMap) to identify transcriptomic profiles of cisplatin-resistant and cisplatin-sensitive cancer cell lines for the purpose of identifying and repurposing FDA-approved compounds as potential otoprotectants against cisplatin-induced hearing loss. Niclosamide, an FDA-approved drug for tapeworm treatment with a favorable safety profile, was identified through this screening method and validated using mice and zebrafish, demonstrating protective effects against cisplatin- and noise-induced hair cell loss and partial protection from hearing loss.
The premise of using transcriptomic profiles of cancer cell lines to model the profiles of inner ear hair cells in response to FDA-approved compounds has not previously been explored and provides a novel screening method to identify potential otoprotective therapies. Yet this reviewer is not entirely convinced the rationale for selecting niclosamide exclusively for further investigation was well reasoned. Additionally, the expansion of this study to further investigate the ability of niclosamide to protect against noise-induced hearing loss seemed far removed from the initial intent of the in silico screens. A more focused and rigorous evaluation of several candidate compounds and their ability to protect against cisplatin ototoxicity would greatly strengthen this study.
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