Androgens, the male sex hormones, fuel the growth of prostate cancer. Cancer growth can be slowed by reducing the amounts of these hormones.
Metastatic prostate cancer has been successfully treated with hormone treatment. Prostate cancer patients who have spread to other parts of their bodies may benefit from anti-hormonal therapy, which works by blocking the signal that testosterone sends to the tumor.
There is a chance that tumor cells will eventually become resistant to this treatment. Scientists from the Netherlands Cancer Institute and other institutions across the world have now disclosed an “unexpected potential” approach that aims to regulate the circadian cycle of cells rather than combat cancer.
Cancer Discovery released the findings on Monday.
Anti-hormonal therapy-mitigating proteins
Prostate cancer can be controlled with anti-hormonal therapy, however, the tumor cells have developed resistance, and thus cancer continues to progress despite the treatment. A more difficult task in treating metastatic prostate cancer will therefore be preventing hormone therapy resistance rather than finding medications that suppress tumor growth.
Researchers from the Netherlands Cancer Institute and Encode Institute uncovered an unexpected discovery using tissue from men with prostate cancer who had been treated with testosterone-inhibiting medicines.
To their surprise, they found that anti-hormonal medication was mitigated by proteins that typically regulate the circadian clock. Wilbert Zwart, one of the researchers, stated in a statement that prostate cancer cells no longer have a circadian rhythm. “Hormonal therapy, on the other hand, gives these “circadian clock” proteins a new purpose in tumor cells, namely the maintenance of cancer cell survival in the face of treatment. First time I’ve ever seen something like this”
Patients with high-risk prostate cancer who had had anti-hormonal medication for three months before surgery were included in the trial. After that, their DNA was analyzed from their tissue samples. For the first time in history, researchers discovered that the genes that kept tumor cells alive despite treatment were controlled by the protein that typically governs the circadian clock.
Prostate cancer anti-hormonal therapy could become even more effective with the discovery of the tumor’s escape route now that researchers have worked with Encode to develop new techniques to inhibit this process.
When it comes to developing new pharmaceuticals to treat prostate cancer, “we will need to start thinking outside the box,” said Zwart. “Medicines that influence the circadian clock proteins to boost the sensitivity to hormonal therapy in prostate cancer,” he added. “As it turns out, anti-hormonal medications can be coupled with therapies that impact circadian proteins. A decade of research could be saved by this lead, which allows for drug repurposing.”
Researchers have discovered a new avenue in the fight against prostate cancer after discovering that inhibiting a circadian protein in prostate cancer cells and mice increases their sensitivity to anti-hormonal therapy.
This study’s findings suggest the possibility that irregularities in the body’s circadian clock increase the likelihood of therapeutic insensitivity in prostate cancer patients. André Bergman, a medical oncologist, remarked, “There is no data to substantiate this.” “There is no circadian clock in prostate tumor cells and the proteins have taken on a completely different purpose. Currently, we are focusing our efforts on finding a way to prevent this new tumor cell escape route in hopes of improving treatment for prostate cancer “He goes on to say.
Androgen receptor-targeting drugs are highly successful in all stages of prostate cancer. However, resistance to therapy is inevitable, and little is understood about how tumor cells can overcome AR repression. Enzalutamide monotherapy for high-risk prostate cancer patients in neoadjuvant clinical trials was studied in this study using tissue samples taken before and after 3 months of AR-targeting treatment. Transcriptomic studies revealed that AR inhibition induced tumors to behave like neuroendocrine tumors. It was discovered that enzalutamide-induced enormous reprogramming of pioneer factor FOXA1 – from inactive to active cis-regulatory elements that control pro-survival signals – was revealed using epigenomic profiling. ARNTL-enriched FOXA1 sites were found in the treatment-induced FOXA1 sites. There was a correlation between ARNTL levels in the post-treatment period and poor outcomes in prostate cancer patients. Following AR-targeted therapy, FOXA1 exhibited extraordinary historic plasticity and established a new dependence on the circadian regulator ARNTL, an intriguing new therapeutic target.