Optimizing High-Dose Testosterone Therapy for the Treatment of Advanced Prostate Cancer
Abstract
Prostate cancer is the most common cancer in men. The success of surgery or radiation therapy for organ-confined disease means that only about 1 in 5 of those men will die of prostate cancer. However, the American Cancer society estimates that prostate cancer will still claim the lives of 29,430 men in 2018, a number much too high. Men with recurrent prostate cancer or cancer that is already metastatic upon initial diagnosis face a difficult battle. Metastatic cancer of any sort poses difficult therapeutic challenges. We believe that strategies we propose can reduce many metastatic prostate cancers to a manageable chronic disease, while maintaining quality of life. Androgen deprivation therapy is the standard of care for men diagnosed with recurrent prostate cancer. This therapy initially promotes regression of metastatic disease, but inevitably the cancer becomes resistant and progression recurs. This is termed castrate-resistant prostate cancer (CRPC), a status with limited therapeutic options. While the use of new and novel hormonal therapies are frequently added on to the initial hormonal therapy, this prolonged very low testosterone state has a high cost in terms of the quality of life and progression is nearly universal. At this juncture, traditional chemotherapy can extend survival by a few months, but at a cost of additional, frequently more severe side effects. The central hypothesis of this proposal is that emerging data shows that a subset of men with CRPC do respond to high-dose testosterone (HDT) therapy. Recently, our center participated in the multi-site TRANSFORMER trial of HDT. This study builds on the results of earlier, smaller studies that provided favorable results. We have now also opened a clinical trial at our institutional to study the use of high-dose transdermal testosterone, which is applied to the skin (“Testosterone Therapy in Castration-Resistant Prostate Cancer” - ClinicalTrials.gov Identifier: NCT03734653). Based on the literature and now our own firsthand experience in using HDT, it is clear that a subset of patients treated with HDT report increased quality of life on testosterone therapy that includes improvements in strength, diminished fatigue, and abrogation of hot flashes that may accompany androgen deprivation therapy. Despite initially favorable responses, we have now seen the development of a new clinical condition in some patients: high-dose testosterone resistance (HTR) that results from tumor adaptation to the testosterone therapy. The overarching goal of this proposal is to identify new approaches to HDT therapy, including the use of combination therapy with other agents, to improve the response rate and duration of response to CRPC patients treated with HDT. We are addressing crucial clinical questions these observations present both from a clinical standpoint (developing improvements to testosterone therapy for CRPC) and, in the preclinical studies proposed here, by identifying the molecular and biochemical changes that mediate progression to CRPC and HTR states. We developed cell culture and animal models of CRPC, as have others, by selecting androgen-dependent LNCaP prostate cancer cells for growth in medium low in androgens. We have also selected CRPC models resistant to the clinically used androgen antagonist, enzalutamide. All of our CRPC models are hypersensitive to androgens and experience cell cycle arrest or apoptosis in response to hormone. To mimic clinical progression to HTR, we have selected multiple CRPC cell line variants that can now grow in high testosterone. These HTR lines regain their sensitivity to androgen deprivation. CRPC lines consistently express markedly increased levels of androgen receptor compared to original LNCaP cells. In contrast, HTR lines derived from CRPC lines express low levels of androgen receptor, much lower than the CRPC lines and even lower than parental LNCaP cells. These changes suggest that repeated cy
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010853
Entities
People
- Thomas Flaig
Organizations
- United States Army
- University of Colorado Denver