Pilot -- Using Peptide Aptamers to Inhibit Smad3

University Of Wisconsin Madison, Madison WI

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Abstract

This Pilot & Feasibility Study examines the intersection of two key pathways that regulate prostate cell growth, differentiation, apoptosis and carcinogenesis. Elevated transforming growth factor beta (TGFbeta) is associated with apoptosis of normal and tumor prostate cells after castration and after pharmacological treatment of benign prostatic hyperplasia. Reduced TGFbeta signaling is associated with hyper-proliferation and malignancy of prostate cells. In contrast, androgens, acting through the androgen receptor (AR), are potent growth stimulators of normal prostate cells and early-stage prostate cancers. Androgen ablation leads to massive apoptosis of prostate epithelial cells. Consistent with their positive effect on cell growth, androgens inhibit TGFbeta's negative effect on prostate cell proliferation. The working hypothesis of this Pilot & Feasibility Study is that inappropriate inhibition of TGFbeta signaling by AR is a causal molecular mechanism in metastatic and non-metastatic hyperproliferation of prostate cells. This imbalance in a normal negative regulatory mechanism may occur in response to environmental factors, aging or tumor progression. To test this working hypothesis, we propose a reverse chemical genetics approach to develop peptide aptamers that specifically inhibit the binding of AR to Smad3, without interfering with other AR functions. Recent studies demonstrated a direct molecular interaction in prostate cells between Smad3, a key intracellular mediator of TGFbeta signal transduction, and AR. Validation of the hypothesis would identify a discrete protein-protein interaction domain that could be used in future drug discovery programs.