Repurposing Itraconazole and Hydroxychloroquine to Target Lysosomal Homeostasis in Epithelial Ovarian Cancer.

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.
Competing Interests: S. Marastoni reports a Canadian patent number 3,116,081 pending. A. Madariaga reports personal fees from Clovis and AstraZeneca outside the submitted work. Z.J. Li reports a Canadian patent number to CA3,116,081 pending. I. Colombo reports personal fees from MSD; other from GSK, AstraZeneca, MSD, Bayer, and Oasmia outside the submitted work. J.P. Bruce reports other from Bowhead Health outside the submitted work. M. Koritzinsky reports other from The Princess Margaret Cancer Foundation during the conduct of the study; in addition, M. Koritzinsky has a Canadian patent number number 3,116,081 pending. B.G. Wouters reports grants from Ontario Institute for Cancer Research, Canadian Institutes for Cancer Research, and Princess Margaret Cancer Foundation during the conduct of the study; other from Northern Biologics outside the submitted work; in addition, B.G. Wouters has a Canadian patent number 3,116,081 issued. A.M. Oza is PI and on clinical trial steer- ing committees for trials with Clovis, GSK, AstraZeneca—all uncompensated. A.M. Oza is uncompensated CEO of Ozmosis Research, a Not For Profit Clin- ical Trials Management company associated with UHN. A.M. Joshua reports non-financial support from Mayne Pharma during the conduct of the study; other from Pricilium outside the submitted work; in addition, A.M. Joshua has a Canadian patent number 3,116,081 pending. S. Lheureux reports grants from OICR - TRI Ovarian Cancer during the conduct of the study; grants and personal fees from AstraZeneca, GSK; personal fees from Eisai, Merck, Shattuck Labs; grants from Roche, and outside the submitted work. No other disclosures were reported.
(© 2022 The Authors; Published by the American Association for Cancer Research.)