From fungus fighter to cancer slayer: itraconazole as a multifaceted candidate for drug-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease state with limited durable responses to existing therapies, including taxane-based chemotherapy. Resistance mechanisms are multifactorial and incompletely addressed by current treatments. Drug repurposing offers an accelerated pathway for the development of novel therapeutic strategies in treatment-resistant disease. METHODS: This review synthesizes preclinical mechanistic data and clinical experience with itraconazole (ITZ), a clinically approved triazole antifungal, across prostate cancer and other malignancies. We evaluate the signaling pathways targeted by ITZ, barriers to its clinical translation, and opportunities for biomarker-driven combination therapy. RESULTS: ITZ functions as a pleiotropic anticancer compound that modulates multiple pathways implicated in prostate cancer progression and therapeutic resistance, including Hedgehog/GLI, PI3K/AKT/mTOR, and Wnt/β-catenin signaling, as well as drug efflux transporters. Preclinical studies demonstrate that ITZ reverses ABCB1-mediated docetaxel resistance, suppresses Hedgehog/GLI1 signaling, and inhibits cancer cell proliferation and invasion. Despite compelling mechanistic rationale, clinical activity in mCRPC has been modest, with limited durable responses, underscoring a translational disconnect. Advancement of ITZ into clinical practice is constrained by pharmacokinetic challenges, dose-limiting toxicities, and the lack of validated predictive biomarkers to identify responsive patient subsets. Emerging evidence further suggests potential synergy with immune checkpoint inhibitors through tumor microenvironment modulation, though this remains unexplored in prostate cancer. CONCLUSIONS: ITZ represents a potential adjunctive strategy to standard therapies within rationally designed, biomarker-stratified combination regimens for mCRPC. Target populations include patients with PTEN-null tumors (elevated Hh/GLI and PI3K/AKT signaling), ABCB1-overexpressing tumors (taxane resistance), or those progressing after AR pathway inhibitor therapy. Clinical advancement will require pharmacological optimization, development and validation of patient stratification biomarkers (GLI1/PTCH1, PTEN status, ABCB1 expression), and integration with therapies targeting complementary resistance pathways.