Evaluation of Androgen Receptor Function in Prostate Cancer Prognosis and Therapeutic Stratification

Background: Innovative approaches are urgently needed to monitor the aberrant function of AR at early stage of prostate cancer, when distinction between indolent and aggressive tumors would have an impact on disease management. AR can be altered via numerous mechanisms; however, the net effect of these changes is reflected in the dysfunction of AR. Unlike in breast cancer where estrogen receptor protein status in primary tumor is effectively used in making therapeutic and prognostic decisions, AR protein expression status does not appear to be useful in stratifying prostate cancer patients by AR status. Thus, knowledge of AR pathway dysfunctions -- what would make prostate tumors refractory to routine androgen ablation -- should help in patient stratification in emerging prognostic strategies.In a recent evaluation of an AR-regulated gene panel in prostate tumor specimens, we reported that attenuation of PSA(KLK3), PMEPA1, NKX3.1, ODC1, AMD1, and ERG gene expression defines a subset of poorly differentiated tumors with biochemical recurrence at the time of radical prostatectomy. Based on the readout of this AR regulated gene panel, we defined AR function by formulating the androgen receptor function index. The selected genes are tightly regulated by AR and altered expression of many of these genes has been causally linked to prostate cancer. We propose here that monitoring AR function by this panel of AR regulated genes will provide a novel approach in the prognosis and stratification of prostate cancer patients on the basis of in vivo functional status of AR.Objective/Hypothesis: The objective of this proposal is to predict the course of prostate cancer progression at the time of radical prostatectomy by monitoring a panel of AR regulated genes in stratifying patients for treatment modalities. We reasoned that in vivo status of AR function in prostate tumor cells can be precisely defined by measuring the expression of a panel of AR-regulated genes.Specific Aims: 1) Establish the AR-regulated gene panel (ARP) as a quantitative measure of in vivo AR functional status in prostate cancer at the time of radical prostatectomy. 2) Define the utility of ARP proteins in monitoring the AR function.Study Design: We have completed comprehensive gene expression analyses of microdissected CaP cells and matched benign cells from 40 patients by microarray studies, as well as by quantitative expression assays with the androgen regulated PSA(KLK3) and PMEPA1 genes in 90 prostate cancer patients. Based on our results and on extensive literature review, a set of six AR-regulated genes were selected. The expression levels of genes in the AR panel will be determined in radical prostatectomy specimens by quantitative real time RT-PCR (TaqMan) and by immunohistochemistry (IHC). Established (in 1993) CPDR-bio-specimen bank linked to comprehensive clinico-pathologic data on patients and longitudinal follow-up will be used for evaluation of AR panel genes in primary prostate tumors. A cumulative index of the quantitative gene expression values and IHC staining scores (AR function index) will be incorporated into established predictive nomograms.Innovation: This proposal will evaluate AR function in prostate cancer tissues by a robust androgen-regulated gene panel developed by our laboratory. The knowledge obtained by this approach will be applied to improve disease prognosis and to stratify patients for specific therapy at the time of radical prostatectomy.Impact: Precise biology-based information obtained from the diseased tissue will improve treatment decision and disease outcome of patients suffering from prostate cancer.Overarching Challenges and Focus Areas: This proposal is in response to the PCRP focus area 'Discovery and Validation of Biomarkers for the Detection, Prognosis, and Progression of Prostate Cancer.' A major challenge of prostate cancer treatment is the lack of a functional-based prognostic stratification of patients at the time of diagnosis and radical prostatectomy. This proposal addresses the utility of a panel of gene and their protein products for monitoring the function of androgen receptor at early stages of prostate cancer treatment towards the prognostic and therapeutic stratification of prostate cancer patients.