TY - JOUR
T1 - Concentration-dependent early antivascular and antitumor effects of itraconazole in non-small cell lung cancer
AU - Gerber, David E.
AU - Putnam, William C.
AU - Fattah, Farjana J.
AU - Kernstine, Kemp H.
AU - Brekken, Rolf A.
AU - Pedrosa, Ivan
AU - Skelton, Rachael
AU - Saltarski, Jessica M.
AU - Lenkinski, Robert E.
AU - Leff, Richard D.
AU - Ahn, Chul
AU - Padmanabhan, Chyndhri
AU - Chembukar, Vaidehi
AU - Kasiri, Sahba
AU - Kallem, Raja Reddy
AU - Subramaniyan, Indhumathy
AU - Yuan, Qing
AU - Do, Quyen N.
AU - Xi, Yin
AU - Reznik, Scott I.
AU - Pelosof, Lorraine
AU - Faubert, Brandon
AU - DeBerardinis, Ralph J.
AU - Kim, James
N1 - Funding Information:
The authors thank Ms. Dru Gray for assistance with article preparation and Steven Wright for assistance with IHC. This study was funded by the Department of Defense Lung Cancer Research Program grants (W81XWH-14-1-0540 to D.E. Gerber and W81XWH-14-1-0338 to J. Kim), NCI grants (K24CA201543-01 to D.E. Gerber and 1R01CA196851 to J. Kim), American Cancer Society grant (RSG-16-090-01-TBG to J. Kim), Cancer Prevention Research Institute of Texas Core Facilities Support Award (RP170003 to W.C. Putnam), Canadian Institutes of Health Research (MFE 140911 to B. Faubert), NCI grant (R35CA22044901 to R.J. DeBerardinis), Cancer Prevention Research Institute of Texas (RP160089 to R.J. DeBerardinis), and the National Heart, Lung, and Blood Institute (5T32HL098040 to S. Kasiri). Additional support was provided by the Biomarker Research Core, Tissue Resource, and Biostatistics Shared Resource in the Harold C. Simmons Comprehensive Cancer Center (P30 CA142543, to principal investigator Carlos Arteaga, MD).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-1916
DO - 10.1158/1078-0432.CCR-20-1916
M3 - Article
C2 - 32847935
AN - SCOPUS:85100846099
SN - 1078-0432
VL - 26
SP - 6017
EP - 6027
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -