Personalized Medicine for Management of Benign Prostatic Hyperplasia
Bechis SK1, Otsetov AG1, Ge R1, Olumi AF2. J Urol. 2014 Feb 25. pii: S0022-5347(14)00304-8. doi: 10.1016/j.juro.2014.01.114. [Epub ahead of print]

Author information

1Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: Olumi.Aria@mgh.harvard.edu.

Abstract

PURPOSE: Benign prostatic hyperplasia (BPH) affects over 50 percent of men by age 60 and is the cause of millions of dollars of healthcare expenditure for treatment of lower urinary tract symptoms (LUTS) and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic BPH, and at least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α reductase Type 2 (5AR2), and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of BPH progression as well as key genes and signaling pathways implicated in the process such as 5α reductase. We also explore the potential of biomarker screening and gene-specific therapies as tools to risk stratify BPH patients and identify those with symptomatic or medically resistant forms.

MATERIALS AND METHODS: A PubMed® literature search of current and past peer-reviewed literature on prostate development, lower urinary tract symptoms, BPH pathogenesis, targeted therapy, biomarkers, epigenetics, 5AR2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined as well as their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications.

RESULTS: BPH is associated with a state of hyperplasia of both the stromal and epithelial compartments, with 5AR2 and androgen signaling playing key roles in development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities play an intricate role in prostate tissue homeostasis as well as its evolution into the clinical state of BPH. Resistance to medical therapy with finasteride may occur through silencing of the 5AR2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5AR2. Novel biomarkers such as single nucleotide polymorshisms may be used to risk stratify patients with symptomatic BPH and identify those at risk of progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate BPH progression and may offer alternative targets for medical therapy.

CONCLUSIONS: Progressive worsening of LUTS and bladder outlet obstruction secondary to BPH is the result of multiple pathways including androgen receptor signaling, pro-inflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene-specific targets. As personalized medicine continues to grow, the ability to risk stratify patients with symptomatic BPH, identify those at higher risk of progression, and seek alternative therapies for those likely to fail conventional options will become the standard of targeted therapy.