Molecular Targeting of Prostate Cancer During Androgen Ablation: Inhibition of CHES1/FOXN3
Abstract
Our operating hypothesis is that checkpoint suppressor 1 (CHES1)/FOXN3 is an androgen withdrawal-induced gene that promotes prostate cancer resistance to apoptosis. The purposes of this research are two-fold. The first is to define the mechanisms of CHES1 gene expression regulation and function, particularly in mediating apoptosis resistance during androgen ablation. Secondly, the tools yielded from our functional studies will be utilized to test the efficacy of CHES1-silencing therapy (CST) in preventing castration-resistant prostate cancer and to develop a mechanism-based noninvasive imaging strategy for monitoring the success of CST. Several significant findings were made. Of major clinical importance, CHES1 expression was elevated substantially during combined androgen blockade and was associated with enhanced PI3K/Akt activation and suppression of pro-apoptotic BNIP3 expression. Conversely, CHES1 down-regulation is potentially necessary for genotoxic stress to trigger apoptosis. To test the hypothesis that CHES1 could be exploited as a therapeutic target, we developed and validated several LNCaP sublines in which we can conditionally silence CHES1 expression, thereby providing us with the necessary models to easily test the value of potential CST. In the coming year, we will test the efficacy of CST to heighten cell killing during androgen ablation and in response to chemotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 10, 2010
- Accession Number
- ADA527747
Entities
People
- Clifford G Tepper
Organizations
- University of California