Small Molecule Therapeutics Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas

We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor–positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague–Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing mPET/CT imaging, employing [18F]-fluor-odeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines includ-ed here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1–3.5 mmol/L). Imaging analysis employing F18-FDG mPET/CT demonstrated a marked reduction of active tumor vol-ume (>75%) after 8 days of letrozole treatment. Immunohisto-chemical analysis revealedmarked reduction in aromatase expres-sion in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aroma-tase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options. Mol Cancer Ther; 14(4); 1–8. 2015 AACR