Do Androgen Receptor Splice Variants Facilitate Growth of Bone Metastases?
Abstract
This project addresses the overarching challenge of mechanisms of resistance and the focus areas of genetics, resistance, and tumor and microenvironment biology. Prostate cancer (PCa) is an androgen-dependent disease. The most common treatment for metastatic PCa is androgen deprivation therapy (ADT). Unfortunately, tumors become resistant to both first and second-line ADT, although there is good evidence that many of them remain androgen receptor (AR) dependent. One of the mechanisms for resistance is expression of variants of AR that lack hormone binding domains. These are always active and are resistant to any of the conventional therapies that target AR. One of the major questions in the field is whether these variants simply substitute for AR or whether they have additional harmful activities. We have made PCa cell models expressing the AR-V7 variant and have compared the genes induced by AR to those induced by the variant. Many are the same, but there are many unique targets too. Some of these changes suggest that the variant may increase growth of bone metastases, one of the most serious problems for patients with CRPC. Our goals are to determine whether expression of variant induces the changes consistent with bone growth in cell lines and to directly test for the ability of the cells to grow when injected into the bone (tibia) of mice. One of the pathways activated by variants, which is known to contribute to tumor growth in bone, is the Notch signaling pathway. If our hypothesis is correct, then we will test Notch signaling inhibitors in vitro to determine whether this pathway is a potential therapeutic target. Notch signaling inhibitors are in clinical trials for breast cancer. If Notch is a variant-dependent pathway, then patients whose tumors express variants may benefit from treatments with inhibitors of this pathway.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510223
Entities
People
- Nancy Weigel
Organizations
- Baylor College of Medicine
- United States Army