ATPS-13: AROMATASE EXPRESSION IN HIGH GRADE GLIOMAS: A POTENTIAL NEW TARGET FOR THERAPY

The prognosis for patients with malignant gliomas remains dismal and novel therapeutic agents are urgently needed. We investigated the potential role of aromatase (CYP19A1), an enzyme that catalyzes the conversion of androgens to estrogens in peripheral tissues, as a target for the treatment of CNS malignancies, as well as brain disposition and anti-tumor efficacy of letrozole, an aromatase inhibitor. Two recent discoveries from our lab have immediate clinical import. First, we analyzed the expression of aromatase in 67 human biopsy samples obtained from the University of Cincinnati Cancer Institute Tumor bank. De-identified frozen tissue samples (containing at least 50 % tumor cells, confirmed by H&E staining) were obtained. These included low grade (LGGs) and high grade gliomas (HGGs) [astrocytomas (N = 12), oligodendrogliomas (N = 10), ependymomas (N = 4), glioblastoma multiforme (GBM, N = 18)], meningiomas (N = 7) and normal brain sections (N = 6). The tissues were analyzed for aromatase expression employing immunohistochemistry. HGGs (N = 35) had markedly higher aromatase expression (> 50%) relative to LGGs (N = 19). It is important to note that all the GBMs (N = 21) showed high CYP19A1 expression, whereas the normal tissues and meningiomas had negligible expression. Secondly, letrozole, a widely used aromatase inhibitor in the treatment of ER+ breast tumors in post-menopausal women exhibited excellent brain and brain tumoral penetration and anti-tumor efficacy (assessed using µPET/CT) in rats orthotopically implanted C6 malignant glioma cells. Furthermore, glioma- bearing rats (N = 10) treated with letrozole (4 mg/Kg; i.p. injections) had long term suppression with overall survival exceeding 65 days and no signs of overt toxicity. In contrast, control untreated rats (N = 6, 2ml/kg vehicle i.p. injections) developed significant morbidity/mortality in 15-20 days. Overall, our studies strongly suggest that aromatase is a new “druggable target” for treatment of HGGs and that letrozole can potentially be readily used for this purpose.