Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer

Area of Science:

• Oncology
• Pharmacology
• Cancer Biology

Background:

• Bevacizumab, an antiangiogenic agent, is approved for non-small cell lung cancer (NSCLC) but offers marginal survival benefits with significant toxicities and costs.
• Endothelial cell proliferation inhibitors are sought for cancer therapy.
• Itraconazole, an oral antifungal, was identified as a potential antiangiogenic agent.

Purpose of the Study:

• To characterize the antiangiogenic and anticancer activities of itraconazole in preclinical models of angiogenesis and lung cancer.
• To evaluate itraconazole's efficacy as a single agent and in combination with chemotherapy.
• To support the clinical translation of itraconazole for NSCLC treatment.

Main Methods:

• In vitro assays assessed itraconazole's inhibition of endothelial cell proliferation, migration, and tube formation.
• In vivo studies utilized primary xenograft models of human NSCLC.
• Tumor vascularity and hypoxia-inducible factor 1 alpha expression were analyzed.
• Combination therapy with cisplatin was evaluated.

Main Results:

• Itraconazole demonstrated potent, specific, and dose-dependent inhibition of endothelial cell functions.
• Oral itraconazole exhibited single-agent growth-inhibitory activity in NSCLC xenografts.
• Itraconazole treatment led to increased tumor hypoxia-inducible factor 1 alpha expression and reduced tumor vascularity.
• Itraconazole significantly enhanced the antitumor efficacy of cisplatin.

Conclusions:

• Itraconazole possesses potent and selective inhibitory activity against tumor-associated angiogenesis both in vitro and in vivo.
• These findings strongly support the clinical use of itraconazole in NSCLC.
• A randomized phase II study is underway to evaluate itraconazole in patients with recurrent metastatic NSCLC.