A new study by an international research team has identified a novel approach to treating prostate cancer by blocking a specific thyroid hormone receptor. The research, led by the Medical University of Vienna, demonstrated that the thyroid hormone receptor beta (TRβ) plays a crucial role in the development and progression of prostate cancer. By inhibiting this receptor, the scientists were able to significantly slow down cancer growth in both cell cultures and animal models. The findings, published in the journal Molecular Cancer, present a promising new therapeutic strategy, particularly for advanced stages of the disease that are resistant to current treatments.
The study focused on the role of TRβ in tumor development and found that the thyroid hormone triiodothyronine (T3) caused a sharp increase in prostate cancer cells. However, when the researchers used a substance called NH-3 to block the TRβ receptor, the growth of cancer cells was significantly reduced. This approach was especially effective in models of castration-resistant prostate cancer, a form of the disease that no longer responds to hormone deprivation therapy. The new method also led to a loss of the androgen receptor signal, which is a key driver of prostate cancer growth. These findings are supported by data from patient cohorts, which showed increased levels of TRβ in prostate tumors compared to healthy tissue.
A Novel Therapeutic Target in Prostate Cancer
The research team, led by Olaf Merkel, Brigitte Hantusch, and Lukas Kenner, identified the thyroid hormone receptor beta as a key driver of prostate cancer growth. Thyroid hormones are known to play a major role in development, metabolism, and energy homeostasis in most tissues. Recent observations, however, have pointed to their involvement in the development and progression of prostate cancer. The new study provides the first direct evidence of TRβ’s role and establishes it as a viable therapeutic target. The researchers found that mutations in thyroid hormone signaling pathways are common in prostate cancer patients, and that the expression of the gene for TRβ is higher in prostate tumors than in healthy tissue.
Mechanism of Action of the TRβ Blockade
The study explored the effects of blocking TRβ both in vitro, using prostate cancer cell lines, and in vivo, using animal models. The researchers used a TRβ-selective antagonist, NH-3, which is currently a research-use-only compound. The results showed that NH-3 effectively inhibited prostate cancer cell proliferation and reduced tumor size.
In Vitro Studies
In laboratory experiments, the researchers treated prostate cancer cell lines (LNCaP and 22Rv1) with the thyroid hormone T3, which led to increased cell proliferation. When they introduced NH-3, it significantly reduced cell proliferation in both cell lines. Binding assays confirmed that NH-3 is highly specific for TRβ and does not inhibit other hormone receptors, such as the androgen receptor, estrogen receptor, or glucocorticoid receptor.
In Vivo Studies
The effectiveness of NH-3 was also confirmed in animal models. In xenograft models using 22Rv1 cells, NH-3 treatment resulted in a dose-dependent inhibition of tumor growth, with up to 80% inhibition at a dose of 3 mg/kg. In LNCaP xenograft models, NH-3 treatment reduced both tumor volume and the uptake of prostate-specific membrane antigen (PSMA), which is an indicator of tumor activity. Importantly, the treatment did not cause any significant side effects, such as weight loss or signs of liver or kidney toxicity, in the animal models.
Implications for Advanced Prostate Cancer
A particularly significant finding of the study is the effectiveness of NH-3 in models of castration-resistant prostate cancer (CRPC). CRPC is a form of the disease that continues to progress despite hormone deprivation therapy, which is a standard treatment for advanced prostate cancer. Effective treatment options for CRPC are currently limited. The study showed that NH-3 was a more effective anticancer agent than enzalutamide, a current standard-of-care treatment for CRPC, and that the two drugs had synergistic properties when used in combination.
Human Data and Future Research
The findings from the laboratory and animal studies are supported by evidence from human datasets. Analysis of whole-exome sequencing data from treatment-naïve prostate cancer patients revealed frequent mutations in genes related to the thyroid hormone signaling pathway. Furthermore, public datasets showed that the messenger RNA levels of the gene encoding TRβ were higher in prostate cancer tumors compared to normal tissues. These results collectively establish TRβ as a mediator of tumorigenesis in prostate cancer and identify NH-3 as a promising therapeutic agent, particularly for castration-resistant forms of the disease. Further research will be needed to validate these findings and to move this new therapeutic approach towards clinical trials.