Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder
outlet obstruction by age 80, rendering benign prostatic hyperplasia (BPH) the most common
proliferative abnormality in humans. LUTS secondary to BPH negatively impact the quality of
life of 210 million men globally, accounting for significant life years lost, in addition to
costing the US healthcare system over $4 billion per year. Medical therapy for the management
of BPH, which includes α-adrenergic blockers (e.g., doxazosin, terazosin, tamsulosin or
alfuzosin) and 5α reductase inhibitors (5ARI, i.e., finasteride or dutasteride) targets both
stromal and epithelial cells in the prostate gland. Utilization of 5ARI remains ineffective
in many patients, leading to invasive therapies in many patients. 5ARI's are the only class
of BPH-related drugs that reduce prostate size for the alleviation of LUTS. However, the
Medical Therapy of Prostatic Symptoms (MTOPS) trial, which randomized 3047 men, showed that
34% of BPH patients did not respond to individualized treatment with finasteride or
doxazosin, while combining the 5ARI and α-blocker relieved LUTS in 66% of BPH patients.
Resistance to 5ARI therapy is a major factor limiting the effectiveness of these agents in
the management of BPH. Therefore, understanding the molecular pathogenesis of 5ARI resistance
is a High-Priority Recommendation of the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) Prostate Research Strategic Plan. However, it is not yet possible to
predict responders vs. non-responders to 5ARI therapy, which creates a significant gap in our
ability to effectively manage patients with BPH.
5α reductase (5-AR) plays a critical role in the normal development of the human prostate and
in the pathogenesis and progression of prostatic diseases. There are three types of 5-AR
isozymes, Steroid 5 Alpha-Reductase 1, 2 3 (SRD5A1, SRD5A2 and SRD5A3), which are encoded by
three distinct corresponding genes, SRD5A1, SRD5A2 and SRD5A3. Many studies suggest that all
three 5-AR enzymes are expressed in prostate tissues; however, SRD5A2 is the predominant
enzyme responsible for prostate development and growth. In addition, since the most commonly
prescribed 5ARI, finasteride, is an inhibitor of SRD5A2, regulation of SRD5A2 will remain the
focus of this study.
It was previously shown that the mechanism of somatic suppression of SRD5A2 during adulthood
is dependent on epigenetic changes in the promoter region of the SRD5A2 gene. DNA methylation
is one of the most common epigenetic mechanisms affecting gene expression. Methylation of
Cytosine-Phosphate-Guanine (CpG) islands has been associated with the regulation of genes
during development, cancer initiation, and metastasis. Since the prostate is the only solid
organ that grows during adulthood as a result of androgen exposure, it can be considered a
benign tumor growth throughout adulthood. Therefore, similar to the neoplastic initiation and
progression of many cancers, including prostate cancer, epigenetic changes and variable
expression of SRD5A2 in benign prostate tissue is a plausible molecular mechanism.
Finasteride, the most commonly prescribed 5ARI, is an inhibitor of SRD5A2. Finasteride has
been shown in several large clinical trials to reduce prostate size by 20%, improve urinary
flow rate, and improve urinary bothersome symptom scores in men suffering from bladder outlet
obstruction caused by BPH. Despite their widespread use and clinical effectiveness, 25% to
30% of patients are resistant to the therapeutic effects of 5ARIs and another 5% to 7% of
patients develop worsening symptoms and ultimately may require surgery. Given their age and
comorbidities, these patients are often not ideal candidates for surgery. Therefore,
understanding the mechanisms of 5ARI treatment failure may pave the way for the development
of new medical therapies appropriately targeted to these specific patient groups and is a
desirable way to move forward with precision medicine. This proposed work is based on the
premise that epigenetic changes to SRD5A2 account for the significant number of patients who
are unresponsive to 5ARI therapy. The goal is to assess SRD5A2 methylation and expression as
a gene signature to predict which patients will respond to 5ARI therapy.
The information gained from this proposal will pave the way toward the development of
predictive biomarker assays that can be used to evaluate resistance to BPH-related therapies
and allow clinicians to select alternate therapies for managing the most common proliferative
disorder affecting men worldwide.