The SOX9/Wnt Positive Feedback Loop Is a Novel Therapeutic Target in Advanced Prostate Cancer
Abstract
A major challenge in current prostate cancer (PCa) management is to identify patients with aggressive disease and provide them with more effective and targeted therapy. Accumulating evidence indicates that the SOX9 (Sry-related HMG box 9) transcription factor plays an important role in PCa development, progression, and drug resistance. Increased SOX9 protein expression has been associated with more aggressive PCa (tumor of higher Gleason grades and in castration-resistant/recurrent prostate cancers, CRPC). Reducing SOX9 protein level decreases PCa tumor growth, while overexpressing SOX9 enhances tumor growth and increases tumor invasion. Interestingly, during human fetal prostate development, SOX9 is expressed at the advancing edges of the expanding epithelial branches growing into the neighboring fibrous tissue. Based on these results, we propose that the normal function of SOX9 during fetal development may be hijacked by PCa to drive its invasive growth. Therefore, understanding how SOX9 mediates signal pathways in PCa will provide new clues in solving the puzzle of aggressive PCa. Our studies have discovered that SOX9 stimulates the activity of the WNT/beta-Catenin signal pathway, which also plays important roles in development. With the entering of new WNT/beta-Catenin inhibitors into the clinic, patients with increased WNT/beta-Catenin activity are the ideal subpopulation to benefit from such treatments. This study will define biomarkers to precisely measure WNT/beta-Catenin activity in PCa, which can then be used to identify patients who are most likely to benefit from WNT-targeted therapy. In addition, the therapeutic effects of a group of new and improved WNT inhibitors will be tested in several PCa models, including one that is based on freshly isolated clinical tumors from patients. The outcome will generate a strong basis for near future clinical trials, in which patients with advanced disease will be stratified according to SOX9 and the WNT activity levels based on the biomarkers we will develop. The suitable patients will be treated with WNT inhibitors that have been proved to be effective in our PCa model systems. The findings are highly actionable and extremely valuable in our achieving the overarching goals of eliminating death from PCa and enhancing the well-being of men experiencing the impact of the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510151
Entities
People
- Xin Yuan
Organizations
- Beth Israel Deaconess Medical Center
- United States Army