Scientific Objective and Rationale: Prostate cancer is the most frequently diagnosed male cancer. Treatment of patients with advanced-stage disease relies on hormone-like drugs that target a single, precise region of the androgen receptor (AR), a key protein in the disease. The AR is a good prostate cancer drug target because experience has shown that treatment with the hormone-mimicking drugs frequently leads to a significant remission of the disease. After awhile, however, the cancer comes back because the AR in the tumor changes to be resistant to the hormone-like drugs. Recently, new drugs have been developed to circumvent this resistant state. These "new" drugs are enhanced versions of the original hormone-like drugs that target this same precise region of the AR. While heralded as breakthroughs, the extension in lifespan for men taking these drugs is measured in months. Additionally, the cost of these agents (averaging ~$6,000 per month) is prohibitive and is a significant source of lost time and resources for those patients that do not receive clinical benefit. Our goal is to understand the basis for this resistant state, using a prospectively designed clinical trial at Mayo Clinic termed PROMOTE (PROstate cancer Medically Optimized genome enhanced ThErapy, NCT01953640) as a platform for this understanding. We have discovered that one mode of patient resistance is by tumor cells synthesizing forms of the AR protein that are completely missing the region that is targeted by hormone-mimicking drugs. However, we do not know whether this represents a universal pathway of resistance used by tumor cells in all patients or whether this is a more specific pathway that occurs in a smaller subset of patients. Answering this question is of fundamental importance, because we think it will lead to strategies of predicting whether individual patients will respond or not before they are treated with newer drugs. Moreover, we anticipate our study will motivate our colleagues in academia and industry to move away from the incremental approach of continually retargeting the same precise region of the AR, and force a complete redesign in retargeting strategies.
Approach: PROMOTE will enroll 200 patients that have failed therapy with conventional hormone-mimicking drugs. Patients will undergo multiple-core research biopsies of metastatic tumor tissues prior to receiving abiraterone acetate as standard of care. Men will receive a second metastatic multiple-core research biopsy after 12 weeks of treatment (or earlier if failing treatment). Genetic material will be extracted from biopsy tissues and used for next-generation sequencing studies to identify changes in the AR structure that lead to loss of the precise region targeted by hormone-like drugs. Because we will know the clinical outcomes of the patients enrolled in this trial, we will be able to know if any alterations are associated with favorable or unfavorable responses. We will also grow patient tumor tissue in mice with compromised immune systems, so we can test new experimental therapies against patient-derived tumor cells.
Applicability: The outcome of this research has the potential to help all patients who suffer from prostate cancer, and especially those who may be likely to have resistance to conventional hormone-mimicking therapies, because it may lead to treatments that can be used to prolong their state of remission. But chemicals cannot just be tested on people without first knowing whether and how they are effective. Our goal, therefore, is to lay a sound scientific foundation for the development of these new types of drugs.
Advancing the Field of Prostate Cancer: If successful, the outcome of this work will be knowledge of the alterations that occur in the AR protein that cause resistance to abiraterone acetate. This knowledge is expected to spur other groups to target new regions of the AR protein and lead to a wider variety of potential treatments that might significantly extend the lives of patients suffering from advanced stage disease.
|Effective start/end date||1/1/14 → …|
- Congressionally Directed Medical Research Programs: $725,036.00