Redox Stress-Mediated Inappropriate Androgen Receptor Elevation as a Novel Treatment Paradigm for Castration-Resistant Prostate Cancer
Abstract
Lowering testosterone levels and blocking androgen receptors by androgen deprivation therapy (ADT) in men with prostate cancer is the accepted treatment for more advanced disease (for example, when surgery or radiation is not successful). While ADT causes tumors to shrink, the cancers typically recur in 1-3 years as a highly aggressive form termed "castration-resistant prostate cancer" (CRPC) that often metastasizes. We identified a redox-protective protein that is present in prostate cancer cells and that promotes rapid CRPC growth in mice. The physiologic role of this candidate protein is to protect cells from potentially tissue damaging oxidants helping maintain them at non-harmful levels. Androgen-deprived prostate tumor cells are particularly sensitive to oxidants and therefore inhibition of the candidate protein is a promising strategy, particularly in combination with ADT. We found that the candidate protein is present in high levels in CRPC cells and that depletion of this protein by genetic experiments resulted in profound inhibition of CRPC growth in the context of androgen deprivation. The presence of high levels of the candidate protein in prostate cancer cells is novel, significant, and of high impact because a safe and effective drug that blocks this protein already exists. This compound has been tested and found to be safe in humans in Phase I and Phase II clinical trials for other cancers. However, this compound has never been evaluated in prostate cancer, and our preliminary data suggest a uniquely strong susceptibility to this drug in the CRPC/ADT setting. It has long been known that radiation therapy synergizes with ADT to decrease CRPC tumor growth, ostensibly by increasing oxidant-mediated DNA damage. However radiation therapy has significant systemic side effects. Our proposed treatment paradigm mimics a similar stress as that produced by radiation (increased oxidant production and increased DNA damage) but is expected to have far fewer systemic side effects. Thus, targeting the candidate protein as a combination therapy with ADT is likely to be a safer and better-tolerated option. Furthermore, inhibition of this protein may be overall more effective than radiotherapy as treatment time can be safely prolonged. In addition to investigating the molecular mechanisms of how inhibiting the candidate protein suppresses CRPC cells, we will examine effectiveness of its inhibitory drug in androgen-deprived mouse models representing established CRPC tumors, during progression to CRPC, and after metastasis (including in a clinically relevant bone metastasis model). We will also investigate whether this drug can prevent or inhibit metastatic tumors. Success in any of these clinical situations (CRPC, progression to CRPC, metastasis) would be a major advance in the treatment of prostate cancer in which clinical benefit is measured in months of prolonged survival and not years. Since this drug is already proven to be safe and effective in human clinical trials, this project would be very rapidly translated into the clinic.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610643
Entities
People
- Priyamvada Rai
Organizations
- United States Army
- University of Miami