Targeting BET Bromodomain Proteins: A Novel Therapeutic Strategy for Treatment Resistant Prostate Cancer
About Targeting BET Bromodomain Proteins: A Novel Therapeutic Strategy for Treatment Resistant Prostate Cancer
Prostate cancer is fueled by male hormones or androgens, such as testosterone. Those androgens bind to a protein known as the androgen receptor (AR). When it is activated by binding to androgens, the AR protein becomes a sort of androgen superhighway into the cell’s nucleus where it can act as a regulator of genes, turning them on or off. The vast majority of end-stage, treatment-resistant prostate cancer is driven by such AR “signaling.” Currently many anti-prostate cancer therapies target this AR signaling pathway, attempting to disrupt its pro-cancer activity by blocking either androgen production or blocking the activity of the AR protein itself. However, while responses to such therapies are often robust and extend men’s survival times, ultimately most men will develop resistance to these existing therapies. Drs. Chinnaiyan, Wang and Feng will use this Challenge Award to develop a completely new method of targeting the AR signaling pathway. They will develop an entirely new drug that prevents the genes the AR protein regulates from being turned “on” and making their protein products which act to drive cancer progression. This novel approach to “downstream” targeting of the AR signaling pathway may be used alone or in conjunction with conventional “upstream” anti-androgen drugs such as Zytiga or Xtandi. The researchers believe that such a “downstream” approach may prove more durable and that it will be less likely for men to develop resistance to their novel drug because most mechanisms of resistance are upstream of the drug target.
This team of researchers discovered that the AR physically interacts with a protein (BRD4) in the family of proteins known as BET bromodomain proteins. They also found that after treatment with BET-bromodomain inhibitor, called JQ1, the interaction between AR and BRD4 was blocked and pro-cancer genes downstream of AR were not called into action. They also found JQ1 to be more effective, in animal models of PCa, against tumor growth than Xtandi. While JQ1 is a useful laboratory compound, it does not have optimum drug properties for clinical use. Therefore, Chinnaiyan and his team plan to develop a novel, highly potent bromodomain inhibitor that is best suited to fight advanced prostate cancer with improved potency and drug properties compared to other clinically available bromodomain inhibitors. The team will do all the needed work to bring this highly promising therapeutic advance to a clinical trial in the shortest amount of time possible. They will also design a rational clinical trial that tests their novel drug in patients with advanced PCa that is resistant to conventional therapies.
What this means for patients: While the past few years have seen significant improvements in therapies for treatment-resistant prostate cancer, the overall survival times for men once their disease reaches this advanced stage remains tragically short. Dr. Chinnaiyan and his team will employ an entirely new way to hit back at treatment-resistant prostate cancer by developing, optimizing and functionally evaluating a new class of drug against treatment-resistant PCa. Because this drug works against PCa in a unique way, it may likely be used in conjunction with existing therapies to multiple anti-tumor effects.
Arul Chinnaiyan, MD, PhD (University of Michigan)
Shaomeng Wang, PhD (University of Michigan), Felix Feng, MD (University of Michigan), Irfan Asangani, PhD (University of Michigan).