Jan. 17 2018, Cleveland: Cleveland Clinic researchers have confirmed for the first time a mechanistic link between the gene HSD17B4 and deadly, treatment-resistant prostate cancer.
The research, led by Nima Sharifi, M.D., Cleveland Clinic Lerner Research Institute, Department of Cancer Biology, shows that men who lack a certain subtype of the gene may be more susceptible to aggressive prostate cancer that does not respond to treatment.
Dr. Sharifi and colleagues built upon their earlier seminal work in which they discovered that a gene called HSD3B1, when altered, enables prostate tumors to evade treatment and proliferate. They went on to show that the presence of this gene variant does in fact change treatment outcomes and overall survival in men.
In the current study published in the journal Cell Reports, Dr. Sharifi and his team studied a related gene, called HSD17B4. Previous research showed that HSD17B4 encodes enzymes that inactivate androgens (male hormones). Since androgens are essential for prostate cancer growth, inactivating them should prevent cancer advancement. But these enzymes have also been observed to be more abundant in advanced prostate cancer. Therefore, until now it remained unclear whether the enzymes promote or suppress prostate cancer.
Therapy for advanced prostate cancer–called androgen deprivation therapy (ADT), or chemical castration–blocks cells' supply of androgens, which they use as fuel to grow and spread. While ADT is successful early on, it eventually fails, allowing the cancer to progress to a lethal phase called castration-resistant prostate cancer (CRPC).
"We are hopeful that these findings will lead to more precise and effective treatments for prostate cancer," said Dr. Sharifi. "If men lack a specific isoform of this gene, we may be able to personalize their therapy."
To determine HSD17B4's role in the transition to CRPC, Dr. Sharifi's team analyzed its expression in tissue from patients with healthy prostates, localized prostate cancer and CRPC. They found that HSD17B4 expression levels were relatively the same in benign and local prostate cancer tissue, but significantly reduced in CRPC tissue, suggesting that HSD17B4 does play a role in preventing progression to CRPC.
Through a series of analyses, the researchers found that only one specific isoform of HSD17B4–isoform 2–enzymatically inactivated androgens and prevented tumor growth. It is expressed during the early phases of prostate cancer, but is lost, or suppressed, in CRPC (advanced prostate cancer). Isoforms vary in amino acid sequence and physiological function, but not DNA code.
The team also validated their findings in a preclinical model. Their findings suggest that lack of isoform 2 leads to advanced CRPC. Additional research will be important to determine how HSD17B4 becomes silenced in CRPC and whether it may be used as a biomarker for patients at risk of dying from prostate cancer.
Hyun-Kyung Ko, Ph.D., Department of Cancer Biology, is first author on the study, which was supported by awards and grants from Howard Hughes Medical Institute, Prostate Cancer Foundation, American Cancer Society, and the National Cancer Institute.
Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and co-directs the Cleveland Clinic Center for Excellence in Prostate Cancer Research. He is also a member of the Glickman Urological and Kidney Institute and Taussig Cancer Institute. He has received numerous national awards for his work in uncovering the link between HSD3B1 and CRPC, including the Clinical Research Forum's Top 10 Clinical Research Achievement award in 2017.
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About Cleveland Clinic
Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation's best hospitals in its annual "America's Best Hospitals" survey. Among Cleveland Clinic's 51,000 employees are more than 3,500 full-time salaried physicians and researchers and 14,000 nurses, representing 140 medical specialties and subspecialties. Cleveland Clinic's health system includes a 165-acre main campus near downtown Cleveland, 10 regional hospitals, more than 150 northern Ohio outpatient locations – including 18 full-service family health centers and three health and wellness centers – and locations in Weston, Fla.; Las Vegas, Nev.; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2016, there were 7.1 million outpatient visits, 161,674 hospital admissions and 207,610 surgical cases throughout Cleveland Clinic's health system. Patients came for treatment from every state and 185 countries. Visit us at clevelandclinic.org. Follow us at twitter.com/ClevelandClinic. News and resources available at newsroom.clevelandclinic.org.
About the Lerner Research Institute
The Lerner Research Institute is home to Cleveland Clinic's laboratory, translational and clinical research. Its mission is to promote human health by investigating in the laboratory and the clinic the causes of disease and discovering novel approaches to prevention and treatments; to train the next generation of biomedical researchers; and to foster productive collaborations with those providing clinical care. Lerner researchers publish more than 1,500 articles in peer-reviewed biomedical journals each year. Lerner's total annual research expenditure was $260 million in 2016 (with $140 million in competitive federal funding, placing Lerner in the top five research institutes in the nation in federal grant funding). Approximately 1,500 people (including approximately 200 principal investigators, 240 research fellows, and about 150 graduate students) in 12 departments work in research programs focusing on heart and vascular, cancer, brain, eye, metabolic, musculoskeletal, inflammatory and fibrotic diseases. The Lerner has more than 700,000 square feet of lab, office and scientific core services space. Lerner faculty oversee the curriculum and teach students enrolled in the Cleveland Clinic Lerner College of Medicine (CCLCM) of Case Western Reserve University – training the next generation of physician-scientists. Institute faculty also participate in multiple doctoral programs, including the Molecular Medicine PhD Program, which integrates traditional graduate training with an emphasis on human diseases. The Lerner is a significant source of commercial property, generating 64 invention disclosures, 15 licenses, 121 patents, and one new spinoff company in 2016. Visit us at http://www.lerner.ccf.org. Follow us on Twitter at http://www.twitter.com/CCLRI.
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