Change in prostate tissue gene expression following finasteride or doxazosin administration in the Medical Therapy for Prostatic Symptoms (MTOPS) Study

Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of BPH treatment resistance, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5a-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop drug resistance, which is expected in 33% of finasteride-treated patients. Importantly, a patient's transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patients drug response. Overall design: We defined a case as a patient that resisted treatment and had clinical progression. We defined a control as a patient responsive to treatment and without clinical progression during the trial. We randomly selected 1 responsive control for each resistant case within each treatment arm from within the tissue sub-study. Tissue at baseline and follow-up were from the same side of the TZ. We also selected responsive controls such that the distributions for age (± 3 yrs) and baseline AUA-SI score (± 3 pts) were similar to that of identified resistant cases. We considered individually matching controls to cases, rather than simply matching distributions across groups but determined that any added precision might be small as our focus is on within-individual change in gene expression and MTOPS imposed eligibility constraints on age, clinical characteristics, data collection protocols, and duration of follow-up across all participants. The final study population consisted of 108 MTOPS participants with adequate specimens available in the archive for both baseline and follow-up specimens and with successful RNA extraction and sequencing for both specimens across doxazosin, finasteride, combination, and placebo. RNA was extracted from frozen TZ biopsies at baseline and follow-up. Prior to extraction, excess OCT from each biopsy sample was physically removed on an aluminum block surrounded by dry ice to ensure the tissue does not thaw. Frozen tissue was sectioned to 20 µM slices QIAzol ensuring that the sample is submerged in the liquid and stored at -80C. RNA extraction used the miRNAeasy kit from QIAgen (Item # 69989) following manufacturer instructions. RNA samples were sequenced at Novagene in a blinded manner by Illumina HiSeq 2500 and subjected to quality control using FastQC. RNA reads were aligned to the hg19 genome assembly using TopHat followed by quantification of gene-level raw reads counts using the HTseq.