Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

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Project Summary Prostate cancer depends on androgens and the androgen receptor (AR) for growth and progression. Metastatic tumors are usually initially treated with androgen deprivation therapy by way of medical or surgical castration; however, tumors eventually recur as castration-resistant prostate cancer (CRPC), which progresses due to the intratumoral generation of testosterone and/or dihydrotestosterone and AR stimulation. The identification of these mechanisms and the requirement for sustained AR stimulation has led to the development of enzalutamide, which is a next-generation hormonal therapy that directly and potently antagonizes AR and thereby extends survival for men with metastatic CRPC. Unfortunately, responses to enzalutamide are temporary and resistance eventually leads to death. Enzalutamide resistance is therefore a major and widespread clinical problem for patients with advanced prostate cancer. Recent evidence suggests that enzalutamide resistance is driven by an up-regulation of the glucocorticoid receptor (GR), which re-establishes the expression of 50% of genes that are usually responsive to AR stimulation. Unfortunately, the clinical application of this finding is challenged by the fact that complete and systemic GR ablation is lethal in humans. However, identification of a tumor tissue-specific mechanism that enables GR stimulation might provide a potential therapeutic target that would not compromise the patient. We hypothesize that GR stimulation that occurs with AR antagonist resistance is accompanied by a tumor-specific metabolic mechanism that furnishes abundant local concentrations of cortisol, a GR agonist. Our preliminary data demonstrate that 11β-hydroxysteroid dehydrogenase-2 (11βHSD2), the enzyme that is primarily responsible for cortisol inactivation, is lost with AR antagonist resistance, resulting in augmented local cortisol concentrations. Furthermore, we hypothesize that blocking this metabolic mechanism would reverse GR stimulation and thereby reinstate responsiveness to AR antagonist therapy. Our preliminary data suggest that replacing 11βHSD2 enzymatic function, by either restoring 11βHSD2 expression or blocking the machinery that is required for 11βHSD2 protein degradation, reverses the metabolic phenotype and restores sensitivity to AR antagonist therapy. In Aim 1, we will determine the metabolic phenotype conferred by treatment with next- generation hormonal therapies for CRPC. In Aim 2, we will identify the molecular mechanisms that regulate glucocorticoid metabolism in AR antagonist resistance. In Aim 3, we will determine the therapeutic significance of restoring the baseline metabolic phenotype in AR antagonist resistance. Together, these studies will identify and clinically validate mechanisms that drive AR antagonist resistance. It is anticipated that this work will lead to the identification of tumor-specific mechanisms of resistance to next-generation hormonal therapies that are pharmacologically targetable and to the eventual development of new treatment strategies for the lethal form of prostate cancer.