Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas
High grade gliomas (HGGs) remain highly fatal malignancies with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly.  Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population.   Our pre-clinical studies suggest that the expression of CYP19A1, that encodes aromatase, is significantly upregulated in HGGs and that letrozole (LTZ), an FDA approved aromatase inhibitor, has marked activity against HGGs.   We conducted a phase 0/I single center clinical trial to assess the tumoral availability, pharmacokinetics (PK), safety and tolerability of LTZ in recurrent HGG patients.  Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5 and 20 mg of LTZ administered daily pre- and post-surgery or biopsy.  Tumor samples were assayed for LTZ content and relevant biomarkers. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-seq analysis. Overall design: Patient tumor samples from 2.5 mg (Group 1), 5 mg (Group 2) and 10 mg (Group 3) dose-cohorts, and three control samples were processed for mRNA isolation via poly-A RNA purification. The mRNA libraries were prepared, indexed, and pooled in order to obtain 50-100 million reads per sample. Sequencing of libraries for 50 bp was performed using the Illumina HiSeq system. Data were de-multiplexed, and appropriate quality control checks were performed before aligning the sequences to the human reference genome (hg19) using TopHat2 aligner.