Hormonal therapy in prostate cancer is like a dynamic game of chess. Male hormones, called androgens, drive and sustain the cancer. Androgen deprivation therapy – shutting off testosterone with drugs such as leuprolide or goserelin – can slow or even stop this growth.

However, prostate cancer is resourceful: it can latch onto proteins called androgen receptors (AR), and use them to make the fuel it needs to grow. AR signal-blocking drugs such as enzalutamide and abiraterone shut down this path.

But once again, cancer can rally, by creating a slightly different AR (called an AR-splice variant) that doesn’t respond to these drugs. (Several variants, including one called AR-V7, have been identified at the Brady by Jun Luo, Ph.D., the Alan W. Partin, M.D., Ph.D., Professor of Urology.)

“When cancer becomes resistant to these therapies, it evolves into a more aggressive form, known as castration-resistant prostate cancer (CRPC),” says scientist Sushant Kachhap, Ph.D. “There is a need for new approaches that can target these variants and other mechanisms that encourage the AR in CRPC, to make treatment more effective.”

In exciting research, Kachhap and colleagues may have found one. A new study from his lab, published in Federation of American Societies of Experimental Biology (FASEB), focuses on a protein called CRM1, “which plays a role in stabilizing the AR at both the RNA and protein levels,” Kachhap explains. “This is especially important, because AR-splice variants originate at the RNA level.”

CRM1, it turns out, is an important linchpin that keeps the wheel of advanced prostate cancer turning. By using a drug called Selinexor, which targets CRM1 and is already approved for treating other cancers, Kachhap’s team was able to destabilize both the AR protein and AR variants in prostate cancer cells. “Selinexor works by preventing the transport of proteins that keep the AR, ultimately inhibiting its function.”

“What’s even more promising,” Kachhap continues, “is that CRM1 also influences other cancer-associated proteins and pathways, including DNA repair. Targeting CRM1 offers new opportunities for innovative drug combinations beyond traditional hormonal therapy. Although further research is needed to test this approach in pre-clinical models, the early signs are very encouraging.” This work was supported by the Patrick C. Walsh Prostate Cancer Research Fund and by the Department of Defense."