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Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non-Small Cell Lung Cancer
David E Gerber1,2,3, William C Putnam4, Farjana J Fattah5
1Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. david.gerber@utsouthwestern.edu.
Purpose:
Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients.
Experimental Design:
Patients with non-small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10-14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers.
Results:
Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, -0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, -0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, -0.73; P = 0.01) and GM-CSF (Spearman correlation, -1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, -0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations.
Conclusions:
Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Insights
Itraconazole shows anticancer effects in non-small cell lung cancer (NSCLC) by reducing tumor volume and blood vessel growth. Interpatient differences in drug concentration are key to its effectiveness.
Area of Science:
- Oncology
- Pharmacology
- Translational Medicine
Background:
- Itraconazole, an antifungal, is being investigated as an anticancer agent.
- Preclinical studies suggest itraconazole possesses antiangiogenic and Hedgehog pathway inhibitory properties.
Purpose of the Study:
- To assess the biological impact of itraconazole in human patients with non-small cell lung cancer (NSCLC).
- To evaluate the antiangiogenic and pathway-modulating effects of itraconazole in a clinical setting.
Main Methods:
- A window-of-opportunity trial involving NSCLC patients scheduled for surgery.
- Administration of itraconazole (300 mg BID) for 10-14 days prior to resection.
- Dynamic contrast-enhanced MRI, plasma and tissue biomarker analysis for pharmacokinetics, pharmacodynamics, and pathway activity.
Main Results:
- Itraconazole was well-tolerated, with significant interpatient variability in plasma concentrations.
- Higher itraconazole levels correlated with reduced tumor volume, perfusion, proangiogenic cytokines (IL1b, GM-CSF), and microvessel density.
- Tumor metabolic profiles were altered, but Hedgehog pathway gene transcription (GLI1, PTCH1) remained unchanged.
Conclusions:
- Itraconazole exhibits concentration-dependent antivascular, metabolic, and antitumor effects in NSCLC patients.
- Interpatient pharmacokinetic and pharmacodynamic variability should be considered for fixed-dose cancer therapies.
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