Prostate cancer is the most commonly diagnosed malignancy and one of the leading causes of death from cancer among American men. As estimated, this disease accounts for 33% of all cancers diagnosed in men and 9% of male cancer-related deaths in 2006. Unfortunately, there are no effective drugs or protocols that can cure the advanced form of this fatal disease, and the etiology of prostate cancer is largely unclear.
In human cancer, one group of genes (tumor suppressors) that function normally in suppressing tumor formation is often found inactivated, and another group of genes (oncogenes) that act as tumor promoters is usually overactivated. The protein CBP is important for gene transcription. An important enzymatic property of this protein is the ability to transfer a small molecule (acetate) onto other proteins (for example, histones). This enzymatic activity, called histone acetyltransferase (HAT), of CBP modulates gene transcription. Expression of CBP is often lost or decreased in human prostate cancer. Clinical trials have demonstrated that counterbalancing the loss of HAT in tumor cells with histone deacetylase inhibitors reduces tumor growth in patients. p27KIP1 is a cell proliferation inhibitor. Decreased expression of this protein is often correlated with outcome of prostate cancer. Therefore, both CBP and p27KIP1 are highly relevant tumor suppressors in prostate cancer. However, their roles in the development, progression, and treatment of prostate cancer are largely unknown.
In this proposal, we will recapitulate the deletion of CBP and p27KIP1 specifically in the mouse prostate by generating a double-knockout mouse model for human disease. Monitoring and characterization of tumors in a stage-defined manner will enable us to document the molecular events that otherwise cannot be detected in human prostate cancer. A number of advanced techniques, including digital image analysis of nuclear morphometry and gene transcription profiling, will be applied to detect malignant changes at a very early stage in this unique mouse model.
In order to explore the utility of the CBP/p27KIP1 double knockout mouse model in the treatment of prostate cancer, we will examine the anticancer efficacy of SAHA and bortezomib, two potent drugs that are under investigation in clinical trials. SAHA inhibits the activities of histone deacetylases and thus can counterbalance the lost HAT activity of CBP. Bortezomib inhibits the activities of proteasomes. We anticipate this drug will block the degradation of p27KIP1 protein.
In summary, we will utilize several advanced techniques to characterize this stage-defined and disease-related model system in order to identify markers useful for early tumor detection. We will test directly whether loss of CBP and p27KIP1, as a molecular signature, can be targeted for the treatment of prostate cancer.
|Effective start/end date||1/1/06 → 12/31/06|
- U.S. Department of Defense: $548,844.00