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

<ns3:p>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.</ns3:p>