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.
