An international team of researchers led by the Medical University of Vienna has, for the first time, shown that thyroid hormone receptor TRβ (thyroid hormone receptor beta)*, also known as nuclear receptor subfamily 1, group A, member 2 (NR1A2), is a nuclear receptor protein that in humans is encoded by the THRB gene, plays a key role in the development and progression of prostate cancer.
By blocking this specific thyroid hormone receptor, cancer growth was inhibited in both animal models and tumour cell cultures. The study results, published in the journal Molecular Cancer, thus provide a new approach for the treatment of prostate tumours, especially in a phase where current methods fail.[1]
The research team, led by Olaf Merkel, MD, Associate Professor Brigitte Hantusch, Ph.D., and Professor Lukas Kenner, MD (all from the Clinical Department of Pathology at MedUni Vienna) and first author Aleksandra Fesiuk, MD (Department of Biomedical Imaging and Image-guided Therapy at MedUni Vienna), focused on the role of the thyroid hormone receptor TRβ in tumor development.
In laboratory experiments, activation of the thyroid hormone triiodothyronine (T3) led to a sharp increase in prostate cancer cells. However, when TRβ was inhibited with NH-3, an active substance currently used only in research for the targeted blocking of TRβ, the growth of cancer cells decreased significantly.
This effect was confirmed in animal models: tumors treated with NH-3 remained smaller or developed significantly more slowly. NH-3 proved particularly effective in models of so-called castration-resistant prostate cancer – a form that continues to grow despite hormone deprivation therapy and is currently difficult to treat.
Blocking TRβ also led to a loss of the androgen receptor signal, which is usually activated by male sex hormones and plays a central role in the progression of the disease. Data from patient cohorts support these findings: tissue samples showed increased levels of TRβ in prostate tumors compared to healthy tissue. Furthermore, genetic analyses show that mutations in many prostate cancer patients alter thyroid hormone signaling pathways.
An unmet medical need
Prostate cancer is the 2nd most frequent cancer diagnosed in men, closely following lung cancer. According to data from the American Cancer Society (ACS), each year, approximately 1.5 million men are diagnosed with prostate cancer globally, and more than 300,000 will die of the disease.[2][3]
In its early stages, the disease is usually treated with hormone deprivation therapies (ADT), or androgen deprivation or suppression therapy to lower and reduce the influence of testosterone and dihydrotestosterone (DHT) through either surgical castration or anti-androgen drugs. [4] Second-generation androgen receptor (AR) inhibitors, such as enzalutamide (Xtandi, Astellas and Pfizer), further block AR activity [5]
Although this strategy does not cure prostate cancer, lowering androgen levels often stops or significantly slows the growth of prostate cancer cells. However, approximately 20% patients develop resistance to these therapies, leading to the disease progressing to castration-resistant prostate cancer (CRPC). In turn, within 3 years of diagnosis, nearly 50% of all cases of CRPC advance to metastatic CRPC (mCRPC), resulting in a poor prognosis and severely diminished health-related Quality of Life (hrQoL) [6]
Effective treatment options are currently limited at this stage. The latest findings have identified a previously unknown mechanism that opens up new perspectives.
“Our results suggest that TRβ is not only a driver of tumor growth, but could also serve as a potential target for new drugs,” explained the study leader, Lukas Kenner.
“The study found that combining NH-3 with established androgen receptor inhibitors was particularly interesting, as it showed increased efficacy in preclinical experiments, Kenner concluded.
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Note: * Thyroid hormones play an essential role in growth, development, and metabolism. These are mediated by two different thyroid hormone receptor (TR) isoforms, TRα and TRβ. Thyroid receptors are transcriptional factors that control various genes by interacting with specific co-activators, co-repressors, and DNA sequences.[7]
In humans, TRα is the predominant form of the thyroid receptor in the heart, brain, and bone, while TRβ is mainly expressed in the liver, kidney, and brain. Studies have shown that patients with non-alcoholic steatohepatitis (NASH) display lower TRβ expression in the liver, and more importantly, TRβ agonist treatment decreased liver steatosis and circulating lipids, as well as showed metabolic benefits in preclinical models of diabetes and obesity.[7]
Highlights of prescribing information
Enzalutamide (Xtandi®, Astellas and Pfizer)[Prescribing Information]
Reference
[1] Fesiuk, A., Pölöske, D., de Araujo, E.D. Frere GA, Wright TB, Tin G, Raouf YS, Olaoye OO, Park JS, Blavet N, Tichý B, Schlederel M, Högler S, Wolf M, Philippe C, Aksoy O, Varady A, Mata AM, Varenicja M, Szabó B, Weiss T, Wasinger G, Redmer T, Neubauer HA, Susani M, Spielvogel CP, Ning J, Dahlhoff M, Schepelmann M, Kennedy R, Moriggl R, Brown G, Persson J, Gerner C, Bystry V, Hollóczki O, Heery DM, Gunning PT, Merkel O, Hantusch B, Kenner L.Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer growth. Mol Cancer 24, 256 (2025). DOI 10.1186/s12943-025-02451-2
[2] Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):1893-907. doi: 10.1158/1055-9965.EPI-10-0437. Epub 2010 Jul 20. PMID: 20647400.
[3] McDowell S. Cancer in Men: Prostate Cancer Is #1 for 118 Countries Globally. American Cancer Society (ACS).September 27, 2024. Online. Last accessed on October 19, 2025
[4] Wade CA, Kyprianou N. Profiling Prostate Cancer Therapeutic Resistance. Int J Mol Sci. 2018 Mar 19;19(3):904. doi: 10.3390/ijms19030904. PMID: 29562686; PMCID: PMC5877765.
[5] Blatt EB, Raj GV. Molecular mechanisms of enzalutamide resistance in prostate cancer. Cancer Drug Resist. 2019 Jun 19;2(2):189-197. doi: 10.20517/cdr.2019.25. PMID: 35582713; PMCID: PMC8992629.
[6] Akaza H, Procopio G, Pripatnanont C, Facchini G, Fava S, Wheatley D, Leung KC, Butt M, Silva A, Castillo L, Karavasilis V, Ӧzatılgan A, Hitier S, Ecstein-Fraisse EB, Ӧzgüroḡlu M. Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy: Treatment Patterns From the PROXIMA Prospective Registry. J Glob Oncol. 2018 Sep;4:1-12. doi: 10.1200/JGO.18.00009. PMID: 30260754; PMCID: PMC6223517.
[7] Paguio A, Stecha P, Wood KV, Fan F. Improved dual-luciferase reporter assays for nuclear receptors. Curr Chem Genomics. 2010;4:43-9. doi: 10.2174/1875397301004010043. Epub 2010 May 26. PMID: 21687560; PMCID: PMC3115594.
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DOI
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