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Systematic Review

Repurposing WHO Essential Antifungals for Cancer Treatment - Protocol for a Systematic Review and Cancer Dependency Map Analysis

[version 1; peer review: awaiting peer review]
Kieran Cooper
https://orcid.org/0009-0000-9708-7533
1, Bryan Hennessy1, Cara Osborne2
Kieran Cooper
https://orcid.org/0009-0000-9708-7533
1, Bryan Hennessy1, Cara Osborne2
PUBLISHED 24 Oct 2025
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS AWAITING PEER REVIEW

Abstract

Background

Cancer is a leading cause of mortality worldwide, with rising incidence particularly in low- and middle-income countries (LMICs), where access to affordable treatment remains limited. The high cost of novel drug development highlights the urgent need for alternative strategies. Drug repurposing offers a cost-effective solution by identifying new therapeutic uses for existing medicines with established safety profiles. Antifungal agents share structural and metabolic similarities with cancer cells and have demonstrated anticancer activity in preclinical and early clinical studies. However, current evidence is fragmented, and no systematic review has evaluated the anticancer potential of antifungals included in the World Health Organization (WHO) Model List of Essential Medicines (EML).

Methods

We will conduct a systematic review in accordance with PRISMA 2020 guidelines to synthesise evidence on the anticancer activity of WHO EML antifungals, as well as butenafine. Eligible studies will include in vitro, in vivo, and human clinical research published between January 2015 and June 2025. Outcomes of interest are tumour reduction, apoptosis, survival benefit, or other reported anticancer effects. Data will be extracted in duplicate and risk of bias assessed using RoB 2, ROBINS-I, SYRCLE, or modified ToxRTool as appropriate. A descriptive synthesis will be undertaken, with subgroup analyses by antifungal class and cancer type. Additionally, Cancer Dependency Map (DepMap) data will be analysed to explore in silico antifungal sensitivity across cancer lineages and identify potential mechanisms of action.

Expected outcomes

This study will systematically map the evidence base for antifungal agents in oncology, identify gaps in knowledge, and generate hypotheses for future research. Findings are expected to inform drug repurposing priorities, guide policy in global oncology, and provide a foundation for preclinical and clinical studies investigating antifungals as affordable anticancer therapies.

Keywords

Antifungals; Cancer; Drug repurposing; WHO Essential Medicines; Systematic review; Cancer Dependency Map; Butenafine

Corresponding author: Kieran Cooper
Competing interests: No competing interests were disclosed.
Grant information: The author(s) declared that no grants were involved in supporting this work.
Copyright:  © 2025 Cooper K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Cooper K, Hennessy B and Osborne C. Repurposing WHO Essential Antifungals for Cancer Treatment - Protocol for a Systematic Review and Cancer Dependency Map Analysis [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:112 (https://doi.org/10.12688/hrbopenres.14238.1) First published: 24 Oct 2025, 8:112 (https://doi.org/10.12688/hrbopenres.14238.1) Latest published: 24 Oct 2025, 8:112 (https://doi.org/10.12688/hrbopenres.14238.1)

Background

Cancer remains a leading cause of death globally, with 19.9 million new cases and 9.7 million deaths reported in 2022 alone1. As communicable disease burden declines and populations age, the global cancer burden is expected to rise2. This trend will disproportionately affect low- and middle-income countries (LMICs), where access to effective treatments remains limited. The WHO Model List of Essential Medicines (WHO EML) offers a benchmark for prioritising affordable and evidence-based therapies in resource-constrained settings3. However, many effective anticancer agents remain prohibitively expensive - even in high-income countries - due in part to the $2.6 billion cost of developing a new agent4,5. Drug repurposing offers a promising solution: it identifies new uses for existing medicines with well-characterised pharmacological profiles, thereby reducing development time and cost6.

Antifungal agents have emerged as candidates for repurposing in oncology due to structural and metabolic similarities between fungal and cancer cells7. Several studies have reported anticancer activity of azole antifungals, such as itraconazole and ketoconazole, through mechanisms including angiogenesis inhibition and cell cycle arrest8,9. Our group also has prior data for butenafine, a benzylamine antifungal, suggesting efficacy as an anticancer agent. However, the literature to date is fragmented: studies often focus on single agents or cancer types without a systematic rationale for drug selection or comprehensive synthesis of evidence. Furthermore, no systematic review has evaluated the broader class of antifungals for their potential oncologic use, nor examined those already listed on the WHO EML for repurposing potential.

This study aims to address that gap. By systematically mapping the current evidence base and identifying antifungals on the WHO EML in addition to butenafine, with either established or unexplored anticancer potential, the project seeks to inform future research, prioritisation, and policy development in global oncology.

Study aim and objectives

Aim

Systematically review and evaluate anticancer potential of antifungals.

Objectives, to:

  • - identify and summarise studies investigating WHO EML antifungals including butenafine (+) for cancer treatment.

  • - compare in vitro/vivo anticancer activity of these agents across cancer types.

  • - categorise proposed mechanisms of anticancer action associated with each antifungal.

  • - determine which WHO EML+ antifungals remain unexplored for oncologic use

  • - explore the potential of WHO EML+ antifungals using Cancer Dependency Map (DepMap) data10.

  • Population – cancer cell lines, animal models, human subjects

  • Intervention – antifungal agents (WHO EML+)

  • Comparison – placebo, no treatment, standard treatment

  • Outcome – any anticancer effect

Methods

Study design

We will conduct a systematic review following PRISMA 2020 standards to ensure transparency and methodological rigour. It will identify and evaluate published evidence on the anticancer effects of antifungal agents listed on the WHO EML, as well as butenafine. It will be registered on the Open Science Framework (OSF). The reporting of this protocol is guided by PRISMA-P 2015 and will be published on HRB Open Research and PROSPERO.

Eligibility criteria

We will include primary studies published between 1 January 2015 and 30 June 2025 in peer-reviewed journals or preprint servers. Only English-language studies will be included due to translation resource constraints. Eligible studies must involve:

  • - Study type: In vitro, in vivo, or human clinical research (case reports, series, or trials)

  • - Population: Cancer cell lines, tumour-bearing animals, or patients with malignancies

  • - Intervention: WHO EML antifungals or butenafine, alone or in combination

  • - Outcomes: At least one anticancer effect (e.g., tumour reduction, apoptosis, survival benefit)

  • - Purpose: The antifungal's anticancer potential must be a stated aim

We will exclude studies using non-WHO EML antifungals (except butenafine), those assessing antifungal effects only, studies on healthy or non-cancer models, and those without anticancer outcomes. Non-English articles, reviews, protocols, and editorials will be excluded.

Information sources and search strategy

We will search PubMed, Embase, Web of Science and Scopus (Appendix 2)11. Reference lists of included studies and related reviews will be screened.

Study selection

Two reviewers (KC,CO) will independently screen titles, abstracts, and full texts. Disagreements will be resolved through discussion or adjudication (BH). We will provide a table of excluded full-text studies with reasons. A PRISMA 2020 flow diagram will document the selection process.

Data required and collection

  • - Primary outcomes: anticancer effects.

  • - Secondary outcomes: proposed mechanisms.

  • - Covariates: antifungal class, model type, dosage, concurrent therapies.

  • - Confounders: cancer type, treatment duration, methodological quality.

Data will be extracted independently by two reviewers (KC, CO) using a piloted standardised form. Funding sources and conflicts of interest for included studies will be recorded. Rayyan and EndNote will support record management and reproducibility.

Risk of Bias - Risk of bias will be assessed independently by two reviewers (KC, CO) using:

  • - RoB 2: randomised clinical studies

  • - ROBINS-I: non-randomised clinical studies

  • - SYRCLE: animal models

  • - Modified ToxRTool: in vitro studies

We will assess whether study-level risk of bias may influence pooled interpretation.

Meta-Bias and Confidence in Evidence - Funnel plots will be used to assess publication bias if feasible; otherwise, this will be discussed narratively. GRADE will be used for clinical data; preclinical evidence will be evaluated based on design, consistency, and biological plausibility.

Data Protection - No ethical approval is required as only published data are used.

Analysis Plan - descriptive synthesis will be conducted. Subgroup analysis will explore findings by antifungal class and model type. Discordant findings across studies will be summarised narratively. DepMap analysis will explore in silico antifungal sensitivity by lineage to generate hypotheses using Enrichr (Appendix 4)11. Visual results will support interpretation and dissemination.

Contingencies

Potential challenges include identifying a sufficient number of eligible studies in the systematic review and handling heterogeneous data. If few studies are found, the scope may be expanded to include grey literature or older studies. Technical challenges in DepMap analysis, such as coding errors or dataset inconsistencies, will be mitigated through early training in Python and consultation with bioinformatics support if needed. Training needs include advanced data analysis, visualisation, and reproducible coding practices, which will be addressed through online courses and institutional resources. Any protocol changes will be logged with justification and updated on OSF.

Data availability

All data supporting this systematic review will be derived from publicly available systematic reviews and meta-analyses. No new primary data will be collected.

Extended data11: The following extended data (i.e., supplementary files) are available via -

Open Science Framework, Protocol for a Systematic Review and Cancer Dependency Map Analysis, https://osf.io/gjxw2/11

This project contains the following underlying data:

  • - PRISMA-P Checklist

  • - Appendices

Copyright: © 2025 Cooper K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-By Attribution 4.0 International), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors’ contributions and affiliations

  • Kieran Cooper – RCSI; St James’s Hospital, Dublin (kierancooper96@hotmail.com); conceived review idea and drafted the protocol.

  • Bryan Hennessy - RCSI; Beaumont Hospital, Dublin (bryanhennessy74@gmail.com); contributed to the design and methodological framework.

  • Cara Osborne - The Coombe Women & Infants University Hospital, Dublin (caraosborne97@gmail.com); will assist with screening and data extraction during the review phase.

  • All authors reviewed and approved the final version of the protocol.

References

  • 1.  Ferlay JEM, Lam F, Laversanne M, et al.: Global cancer observatory: cancer today Lyon. France: International Agency for Research on Cancer, 2024. Reference Source
  • 2.  Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388(10053): 1459–544. PubMed Abstract | Publisher Full Text | Free Full Text
  • 3.  World Health Organization: WHO model list of essential medicines. 23rd list Geneva: World Health Organization 2023. May 28, 2025. Reference Source
  • 4.  World Health Organization: Pricing of cancer medicines and its impacts: a technical report for the World Health Assembly resolution 70.12. Geneva: World Health Organization, 2018. Reference Source
  • 5.  DiMasi JA, Grabowski HG, Hansen RW: Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016; 47: 20–33. PubMed Abstract | Publisher Full Text
  • 6.  Siddiqui S, Deshmukh AJ, Mudaliar P, et al.: Drug repurposing: re-inventing therapies for cancer without re-entering the development pipeline-a review. J Egypt Natl Canc Inst. 2022; 34(1): 33. PubMed Abstract | Publisher Full Text | Free Full Text
  • 7.  Weng N, Zhang Z, Tan Y, et al.: Repurposing antifungal drugs for cancer therapy. J Adv Res. 2023; 48: 259–73. PubMed Abstract | Publisher Full Text | Free Full Text
  • 8.  Antonarakis ES, Heath EI, Smith DC, et al.: Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer. Oncologist. 2013; 18(2): 163–73. PubMed Abstract | Publisher Full Text | Free Full Text
  • 9.  Shim JS, Liu JO: Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci. 2014; 10(7): 654–63. PubMed Abstract | Publisher Full Text | Free Full Text
  • 10.  Tsherniak A, Vazquez F, Montgomery PG, et al.: Defining a cancer dependency map. Cell. 2017; 170(3): 564–76.e16. PubMed Abstract | Publisher Full Text | Free Full Text
  • 11.  Cooper KOC, Hennessy B: Protocol for a Systematic Review and Cancer Dependency Map Analysis. OSF, 2025.

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Cooper K, Hennessy B and Osborne C. Repurposing WHO Essential Antifungals for Cancer Treatment - Protocol for a Systematic Review and Cancer Dependency Map Analysis [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:112 (https://doi.org/10.12688/hrbopenres.14238.1)
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