The lethal phenotype of prostate cancer is termed androgen-independent (Al), because it develops following castration in the presence of very low levels of androgen in men or undetectable androgen levels in mouse models. It has been suggested that peptide growth factors, e.g.insulin-like growth factors (IGF) signaling through the IGF tyrosine kinase receptor (IGF-IR), drive the Al phenotype. Recent data clearly demonstrates that androgen receptor (AR) expression is increased in models of Al disease and that in human tissue the AR remains primarily in the nucleus after castration. We have shown inhibition of IGF-IR signaling, with a fully human IGF-IR monoclonal antibody, in androgen- dependent (AD) and Al disease decreases nuclear AR, modifies the AR transcriptional program, and delays emergence of Al disease following castration. In this proposal we will determine the mechanisms of the IGF/AR interaction and efficacy of inhibition of these interactions on human tumors. Hypothesis: Insulin-like growth factor signaling contributes to progression of androgen- dependent [1] and androgen-insensitive [2] prostate cancer progression by enhancing AR nuclear localization and AR signaling.
Aim 1. Determine effect of utilizing a human IGF-IR mab combined with castration in a phase 1b/ll neoadjuvant trial.
This aim will exploit the potential use of IGF-IR blockade using hmabs in association with castration as a potential treatment modality for prostate cancer. In this aim we will utilize both clinical and tissue endpoints.
Aim 2. Aim 2. IGF signaling alters androgen receptor nuclear translocation in prostate cancer through changes in AR phosphorylation. In this aim we will [1] determine if the change in phosphorylation of the AR is associated with an alteration in nuclear import or export of the AR and [2] determine which AR phosphorylation site altered by IGF-IR signaling is responsible for the change in nuclear localization of the AR. [3].Determine the mechanism by which IGF-IR signaling alters AR phosphorylation.
Aim 3. Determine the effects of changes in AR phosphorylation on association of AR co- regulators and changes in AR transcription patterns. In the Preliminary Data, we note that alteration of AR phosphorylation by inhibition of IGF-IR signaling results in an alteration of AR associated co-factors. Most notably among the cofactprs were SMRT and BRCA1. In this aim we will [1], perform a more completed assessment of associated co-regulators, [2] determine effects of co- factors on AR translocation, and [3] determine effects of the associated co-factors on AR transcriptional activity and the AR transcriptional program. The relevance of this study to the goal of improving treatment for prostate cancer is that it will take the laboratory data we have assembled demonstrating that the inhibition of the IGF-IR with a human monoclonal antibody abrogates prostate cancer progression and apply it in a patient setting to determine its potential efficacy in clinical disease.
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