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Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer
Stefano Marastoni1, Ainhoa Madariaga2,3, Aleksandra Pesic1
1Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Abstract:
Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation.
Significance:
The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.
Insights
The antifungal drug itraconazole shows varied efficacy in ovarian cancer cells. Combining itraconazole with hydroxychloroquine demonstrated synergy in vitro by disrupting lysosomal function, but lacked clinical antitumor activity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Drug repurposing offers a viable strategy for developing novel oncology therapeutics.
- Itraconazole, an antifungal agent, exhibits pleiotropic effects beyond ergosterol synthesis inhibition, including modulation of cholesterol metabolism and key signaling pathways like Hedgehog and mTOR.
- Epithelial ovarian cancer (EOC) remains a significant challenge, necessitating exploration of new therapeutic approaches.
Purpose of the Study:
- To evaluate the in vitro activity spectrum of itraconazole across a panel of epithelial ovarian cancer cell lines.
- To identify potential synergistic drug combinations with itraconazole using genome-scale CRISPR screening.
- To assess the safety, feasibility, and preliminary efficacy of combining itraconazole with hydroxychloroquine in patients with platinum-refractory EOC.
Main Methods:
- A comprehensive screening of 28 EOC cell lines was performed to determine sensitivity to itraconazole.
- Whole-genome CRISPR drop-out screens were conducted in two EOC cell lines to identify synthetic lethal interactions with itraconazole.
- A Phase I dose-escalation clinical trial (NCT03081702) investigated the combination of itraconazole and hydroxychloroquine in EOC patients.
Main Results:
- Itraconazole demonstrated a broad range of activity against EOC cell lines.
- In vitro studies revealed synergistic cytotoxicity between itraconazole and chloroquine (an autophagy inhibitor) in EOC cells, associated with lysosomal dysfunction.
- The Phase I trial indicated that the combination of itraconazole and hydroxychloroquine was safe and feasible, but no objective clinical responses were observed, with limited pharmacodynamic effects.
Conclusions:
- Itraconazole exhibits variable sensitivity in epithelial ovarian cancer cells.
- The combination of itraconazole and chloroquine shows in vitro synergistic activity through lysosomal targeting, suggesting potential for lysosome-directed therapies in ovarian cancer.
- While the combination therapy was safe and feasible in a clinical setting, it did not demonstrate antitumor activity in this dose-escalation study.
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