Researchers Identify Potential Therapeutic Target for Advanced Prostate Cancer

Researchers Identify Potential Therapeutic Target for Advanced Prostate Cancer
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Researchers in Spain studying the 3D structure of the androgen receptor have identified a key protein for its activation called TFIIF, making it a possible therapeutic target for advanced prostate cancer.

The study, “Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators,” was published in the journal Structure.

The development and progression of prostate cancer depends on the activation of the androgen receptor (AR) protein. Depriving tumors of androgens such as testosterone or blocking the AR function are common therapies for prostate cancer.

Anti-androgen drugs bind to a specific region of the AR protein and block its activity. But eventually tumors become resistant to such approaches.

“Over time, the protein accumulates alterations and mutates, and there comes a point where it is futile to target this region with drugs because, in fact, it is no longer there,” Xavier Salvatella, the study’s senior author and ICREA researcher at the Institute for Research in Biomedicine (IRB Barcelona), said in a press release.

Patients build up a resistance to these therapies after two or three years, as they develop castration-resistant prostate cancer (CRPC). Whether by increasing AR levels, or through mutations that turn AR resistance to anti-androgen therapy, AR is still activated in CRPC patients.

The clarification of the 3D structure and function of AR domains, along with their interaction with other proteins, has helped in the development of new treatments for the disease.

AR is known to possess a small region that is important for its activation and for the survival of tumor cells. But this region was not considered a potential target for therapies because it was thought to have no relevant structure, which is essential for structure-based drug design.

Now, researchers discovered that this region recruits another protein – TFIIF – and that when it binds to the AR it forms a helix shape. The binding of TFIIF to this region on the AR was shown to stimulate the activity of AR, and the deletion of that region reduced its activity by 30 percent.

Overall, the study’s results revealed that this interaction, and specially TFIIF, is a potential therapeutic target for CRPC.

“The fact that TFIIF is a folded protein with a more defined structure makes it easier to search for drugs that can interfere with its interaction with the motif,” Salvatella said.

“For prostate tumor cells that have become resistant to treatment, we believe that this interaction could be their last mechanism through which to survive and proliferate,” he added.

Elzbieta Maria Szulc, co-first author of the study, said that “using cells in vitro, we have seen that if we remove this region, the TFIIF protein can’t bind to the androgen receptor. So if the interaction does not occur, the androgen receptor loses activity, which is what we are interested in achieving.”

The team is already searching for drug therapies that interfere with TFIIF, with the help of computational modeling experts. “We don’t know whether such drugs will have a positive effect on cells, but the data available is promising,” Salvatella said.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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