Researchers at the University of Eastern Finland have made important discoveries that could lead to better treatments for drug-resistant prostate cancer. Their findings, recently published in two separate studies, shed light on how a specific protein called the glucocorticoid receptor plays a role in the development of drug resistance in prostate cancer cells.
Glucocorticoids are a type of steroid hormone that are commonly used as anti-inflammatory drugs and to help cancer patients manage the side effects of their treatments. However, recent studies have shown that the glucocorticoid receptor, which helps cells respond to these hormones, can also promote the growth of certain cancers, including prostate cancer.
“Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer,” says Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland.
In their first study, published in Nucleic Acids Research, the researchers found that the glucocorticoid receptor can replace the activity of another protein called the androgen receptor, which is the main driver of prostate cancer growth. This happens when the androgen receptor is blocked by drug therapy, allowing the glucocorticoid receptor to step in and help the cancer cells develop resistance to the treatment.
“This study showed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells,” explains Doctoral Researcher Laura Helminen of the University of Eastern Finland.
The researchers initially thought that by inhibiting a protein called FOXA1, which is known to promote cancer growth, they could limit the development of drug resistance mediated by the glucocorticoid receptor. However, they were surprised to find that inhibiting FOXA1 actually increased the activity of the glucocorticoid receptor, because FOXA1 is involved in silencing the glucocorticoid receptor gene.
In their second study, published in Cellular and Molecular Life Sciences, the researchers explored an alternative approach to inhibiting the effects of the glucocorticoid receptor by targeting coregulator proteins, specifically EP300 and CREBBP.
“Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells,” says Project Researcher Jasmin Huttunen of the University of Eastern Finland.
By inhibiting these coregulator proteins, the researchers were able to slow the growth of drug-resistant prostate cancer cells. They also found that this approach effectively inhibited the activity of the androgen receptor, especially in prostate cancer cells with an amplification of the androgen receptor gene, which is found in up to half of patients with advanced prostate cancer.
Interestingly, the EP300 and CREBBP inhibitor also blocked the activity of FOXA1 while still allowing it to silence the glucocorticoid receptor gene, preventing the development of drug resistance mediated by the glucocorticoid receptor.
These findings offer new hope for patients with drug-resistant prostate cancer, as targeting coregulator proteins could potentially provide an effective treatment option. Several pharmaceutical companies are already developing small-molecule inhibitors that target EP300 and CREBBP, with some currently being studied in patients.
The research was funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland, and highlights the importance of continued investment in cancer research to improve patient outcomes and quality of life.
