Understanding the Relative Contributions of and Critical Enzymes for the Three Pathways for Intracrine Metabolism of Testicular Androgens in Advanced Prostate Cancer
Abstract
Prostate cancer growth and recurrence relies on the relationship between the androgen receptor (the lock) and androgens (the key). The strong testicular androgens, testosterone and dihydrotesterone, activate the androgen receptor to drive prostate cancer development and growth. Most men with advanced prostate cancer are treated with hormone therapy. Hormone therapy lowers circulating testosterone to castrate levels, which starves prostate cancer of testosterone necessary to activate the androgen receptor, and causes prostate cancer remission. However, hormone therapy is not curative; prostate cancer recurs and causes death. One reason for prostate cancer recurrence is tumors use up to three alternative pathways to make strong testicular androgens during hormone therapy. These pathways have several steps, and the progression of each step relies on the activity of proteins called enzymes. Enzymes convert weak adrenal androgens or other steroid molecules into molecules that advance along the steps of the three alternative pathways to make the strong testicular androgens. Drugs, like abiraterone or dutasteride, target enzymes to block their activity and stop the progression of steroid molecules along the pathways to strong testicular androgens. For example, abiraterone blocks an enzyme involved in the early steps of all three pathways. However, at least five ways of overcoming the effect of abiraterone have been described, which limits the effectiveness of abiraterone to extending survival by only about 4 months when used late in prostate cancer treatment. A second example is dutasteride, which blocks all three enzymes that convert testosterone to dihydrotestosterone, the stronger of the two testicular androgens. Even though dutasteride blocks the enzymes needed to prevent the last step in one of the pathways, prostate cancer cells adapt and make strong testicular androgens using different enzymes that convert steroid molecules in the last steps in the other two pathways. The last steps in all three pathways depend on up to five enzymes to make strong testicular androgens. These enzymes have a common activity site that can be targeted using drugs. Therefore, the goal of our studies is to define what drives the switch from one pathway to another, isolate the key enzymes involved with each of the pathways, and show that blocking enzyme activity involved with critical steps (probably the later steps) in each pathway will prevent prostate cancer adaptation to and growth during hormone therapy. Aim 1 will use prostate cancer cell lines and fresh surgical human prostate cancer tissue to determine which of the three pathways is the dominant pathway before and after hormone therapy. The use of each pathway by prostate cancer will be determined by measuring conversion of un-labeled steroid molecules and fluorophore (molecules that emit color)-labeled steroid molecules. Aims 2 and 3 will identify the most critical enzymes for each of the last conversion steps for any of the three pathways used. The research plan uses sophisticated modeling similar to that used to model traffic and the effect of an accident or the building of a new road to see how fluorescent steroids (the cars) move through the three alternative pathways (the roads) to strong testicular androgens (the destination) and how this is affected by hormone therapy (loss of all traffic lights) or inhibiting an enzyme (closing a road). A proof-of-principle study will be conducted using prostate cancer cell lines implanted into laboratory animals to test whether inhibiting the later steps in each pathway will lower the levels of strong testicular androgens, cause prostate cancer cell death, decrease adaptation to hormone therapy, and decrease growth and recurrence of prostate cancer during hormone therapy. The potential clinical application of the proposed research is to provide new and better drugs that overcome the limitations of abiraterone or dutasterid
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610635
Entities
People
- David S Watt
Organizations
- United States Army
- University of Kentucky