An Innovative Approach to Extinguish Androgen Receptor (AR) Axis Signaling in Prostate Cancer
Abstract
Despite significant advances in treatment options, ~30,000 men die of prostate cancer in the United States annually, making it the second leading cause of cancer death in US men. In order to develop more effective treatments, we need to address the mechanisms that allow prostate cancers to escape from current therapies. Prostate cancer growth requires testosterone, which (after conversion into dihydrotestosterone) activates a protein called androgen receptor. So far, the main treatment for advanced prostate cancer has been to decrease testosterone production. This treatment is usually effective initially, but eventually the cancer grows back again, even though testosterone levels in the rest of the body are very low. These treatment-resistant prostate cancer cells frequently produce high amounts of androgen receptor proteins that can function even in low-testosterone conditions (called "ligand-independent" androgen receptors, including those "splice variants" that were discovered in recent years) and drive cancer growth. Unfortunately, even new drugs, such as abiraterone and enzalutamide, are inactive against prostate cancers that produce high amounts of "ligand-independent" and "splice variant" androgen receptors. Therefore, more effective therapies for prostate cancer are urgently needed. We have discovered that a protein called GATA2 is necessary both for the production of androgen receptor and for its full activity. This makes GATA2 a very important new therapeutic target for prostate cancer. In this proposal, we aim to establish a new treatment approach for advanced prostate cancer via innovative drugs that will inhibit GATA2 and will deliver two hits to prostate cancer cells: they will decrease the levels of androgen receptors present in the cancer, as well as inactivate any residual androgen receptor. We have identified two such compounds designed to inhibit GATA2. The first, called K7174, was previously designed to treat diseases of inflammation, but has never been used to treat prostate cancer. Our group at Baylor College of Medicine has synthesized K7174, and we found that it can suppress the growth of prostate cancer cells cultured in the lab. However, high concentrations of this compound were needed for anticancer activity in these lab experiments, so it remains unknown how effective K7174 will be against prostate cancer in patients. Therefore, we now propose a series of experiments to examine the activity of K7174 in mouse models of prostate cancer, which represent one step closer to clinical prostate cancer. Another direction that we propose is to examine the second GATA2 inhibitor, K11706, which was also previously designed to treat diseases of inflammation and anemia and was reported to be 1000 times stronger than K7174. Similar to K7174, K11706 has never been tested so far as an anticancer agent, and we now propose to examine its activity against human prostate cancer cells cultured in the lab, as well as in mouse models of prostate cancer. Therefore, our proposed studies are quite innovative, as they will attempt to treat prostate cancer using an entirely new approach (inhibition of GATA2) and two compounds (K7174 and K11706) that have not been previously used to treat this disease. We anticipate that patients with advanced prostate cancer, in particular those that no longer benefit from the standard hormonal therapies or the newer drugs abiraterone and enzalutamide, will substantially benefit from this innovative approach. Because the compounds K7174 and K11706 are already synthesized, our results can be quickly translated into future clinical trials within a few years if they exhibit activity against prostate cancer in our studies. Alternatively, if our studies demonstrate that this novel approach is promising but neither of these two compounds is active enough for use in patients, then our group has the capacity to design and synthesize additional compounds in order to improve thei
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510674
Entities
People
- Nicholas Mitsiades
Organizations
- Baylor College of Medicine
- United States Army