Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

项目摘要 前列腺癌的生长和发展依赖于雄激素和雄激素受体(AR)。 转移性肿瘤最初通常通过内科或外科的方式去雄激素治疗。 去势；然而，肿瘤最终复发为去势抵抗型前列腺癌(CRPC)，它的进展是由于 对肿瘤内产生睾酮和/或双氢睾酮和AR的刺激。身份识别 这些机制和对持续AR刺激的要求导致了 苯扎鲁胺，这是下一代激素疗法，直接和有效地拮抗AR，从而 延长转移性慢性前列腺癌患者的生存期。不幸的是，对苯扎鲁胺的反应是暂时的 抵抗最终会导致死亡。因此，对苯扎鲁胺的耐药性是一个主要和普遍的临床问题。 适用于晚期前列腺癌患者。 最近的证据表明，苯扎鲁胺的耐药性是由糖皮质激素上调所致 受体(GR)，它重建通常对AR刺激有反应的50%的基因的表达。 不幸的是，这一发现的临床应用受到了以下事实的挑战：完整和系统性的GR 消融对人类来说是致命的。然而，肿瘤组织特异性机制的鉴定使GR 刺激可能提供一个潜在的治疗靶点，而不会损害患者。 我们假设，AR拮抗剂耐药时发生的GR刺激伴随着 肿瘤特异性代谢机制，提供丰富的局部浓度的皮质醇，GR激动剂。我们的 初步数据表明，11β-羟基类固醇脱氢酶-2(11βHSD2)是一种主要 负责皮质醇失活，由于AR拮抗剂耐药而丢失，导致局部皮质醇增加 浓度。此外，我们假设阻断这一代谢机制将逆转GR 刺激，从而恢复对AR拮抗剂治疗的反应性。我们的初步数据表明 通过恢复11βHSD2的表达或阻断11βHSD2的机制来取代11 HSD2的酶功能 是11β热休克蛋白降解所必需的，逆转代谢表型并恢复对AR的敏感性 对抗疗法。在目标1中，我们将确定NEXT-1治疗所产生的代谢表型。 CRPC的一代激素疗法。在目标2中，我们将确定调节 糖皮质激素代谢在AR拮抗剂耐药中的作用在目标3中，我们将确定其治疗意义 在AR拮抗剂耐药中恢复基线代谢表型。总而言之，这些研究将确定 并在临床上验证AR拮抗剂耐药的机制。预计这项工作将导致 以确定肿瘤特异性抵抗下一代激素疗法的机制，这些激素疗法 在药理学上具有靶向性，并最终开发出针对致命性形式的 前列腺癌。

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.