Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in > 25 fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts; however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti-androgen response document this is due to AR binding to replication complexes (RC) at origin of replication sites in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilizes preventing sufficient degradation in mitosis inhibiting DNA re-licensing and thus death in the subsequent cell cycle. These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing.

A proteomic analysis of islets was undertaken to determine the protein constituents of normal adult mouse islets. Unexpectedly, we identified several islet proteins that are associated with the pathogenesis of Alzheimer's disease. Some of these proteins had chaperone activity that is integral to proper protein folding. This group includes GRP78, valosin-containing protein, calreticulin, protein disulfide isomerase, DnaK, HSP70, HSP60, and TCP-1. Additionally, neuronal proteins key to coordinated neuronal guidance and survival were also identified in islets. This group includes proprotein convertase subtilisin, collapsin response mediator protein 2, ubiquinol-cytochrome c reductase core protein, L-3-hydroxyacyl-Coenzyme A dehydrogenase, glutamine synthetase, peroxiredoxin, and secretogogin. An important subset of the proteins identified here has not been reported previously in pancreatic islets. Abnormal activity of these proteins in brain may contribute to the pathogenesis of Alzheimer's disease, a neurodegenerative condition characterized by focal amyloid deposits with neurofibrillary tangles. The putative role of these proteins in Alzheimer's pathogenesis is intriguing given the possible clinical relationship and pathological similarity of Alzheimer's disease to type 2 diabetes. These findings have therefore led to the hypothesis that these proteins may also play a role in type 2 diabetes.

These findings contribute greatly to our understanding of androgen-independent prostate cancer. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the adaptive response to androgen deprivation; it provides a more dynamic illustration of genes which contribute to disease progression in addition to specific genes which constitute an androgen-independent phenotype.