TRAF4 and Castration-Resistant Prostate Cancer
Abstract
Most prostate cancer patients progress to castration-resistant disease after initial response to androgen deprivation therapy. Docetaxel-based chemotherapy is the standard treatment for these patients. However, virtually all of them develop resistance to the therapy or cannot tolerate toxicity after short-term benefit. Thus, there is an urgent need to develop a novel therapeutic approach. Molecular targeted therapies have been successful in treating certain cancers with specific oncogenic alteration, such as trastuzumab for targeting HER2-overexpressing metastatic breast cancer and gefitinib for targeting EGFR mutations in lung cancer. In order to develop a similar therapeutic strategy for prostate cancer, important molecules and signaling pathways in prostate cancer progression need to be identified. Androgen is the primary stimulator for prostate cancer proliferation. Androgen ablation induces prostate cancer cell apoptosis or cell cycle arrest. The mechanism of androgen-independent prostate cancer development usually involves alteration of androgen receptor signaling, growth factor signaling, or evasion of cell apoptosis upon androgen deprivation. Using a high-throughput screening approach, we identified a novel gene TRAF4 that is important for androgen-independent growth of prostate cancer cells. TRAF4 is upregulated in metastatic and hormone refractory prostate tumors compared to benign or primary tumors. Preliminary data indicated that TRAF4 alters AR post-translational modification and promotes a switch of AR function towards androgen-independent prostate cancer growth. In addition, TRAF4 is an enzyme and it is a druggable target. These results suggest that TRAF4 may serve as a potential therapeutic target. The proposed study will enrich our understanding on a relatively new class of signal molecules that influence castration-resistant prostate cancer progression. Given the fact that TRAF4 is overexpressed in 50%-60% of prostate cancer patients, developing specific target therapies against TRAF4 could be beneficial for patients who have high levels of TRAF4 protein. Considering its anti-apoptotic function, targeting TRAF4 may also sensitize chemotherapy responses, which are dependent on apoptosis for cell killing, in a specific group of patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510536
Entities
People
- Ping Yi
Organizations
- Baylor College of Medicine
- United States Army