Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌

• 批准号: 10521260
• 负责人: Nima Sharifi
• 金额: $ 7.35万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-06-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10521260
• 关键词: AR gene; Ablation; Agonist; Androgen Receptor; Androgens; Cancer Etiology; Castration; Cessation of life; Clinic; Clinical; Data; Development; Enzymes; Generations; Genes; Glucocorticoid Receptor; Glucocorticoids; Growth; Hexoses; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; Ligands; Malignant neoplasm of prostate; Mediating; Medical Castration; Metabolic; Metabolism; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Oxidoreductase; Pathway interactions; Patients; Proteins; Receptor Up-Regulation; Recurrence; Resistance; Stanolone; Testosterone; Therapeutic; Therapeutic Effect; Tumor Tissue; United States; Up-Regulation; Work; advanced prostate cancer; androgen deprivation therapy; androgen sensitive; antagonist; castration resistant prostate cancer; clinical application; cofactor; enzalutamide; enzyme activity; hormone therapy; improved; inorganic phosphate; insight; men; metabolic phenotype; new therapeutic target; next generation; novel therapeutic intervention; pharmacologic; protein degradation; protein expression; receptor upregulation; reconstitution; resistance mechanism; response; restoration; standard of care; targeted agent; therapeutic target; treatment strategy; tumor; tumor metabolism; tumor progression

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.

项目摘要 前列腺癌的生长和进展依赖于雄激素和雄激素受体（AR）。 转移性肿瘤通常最初通过药物或手术的方式用雄激素剥夺疗法治疗。 然而，肿瘤最终复发为去势抵抗性前列腺癌（CRPC），其进展是由于 肿瘤内产生睾酮和/或二氢睾酮以及AR刺激。识别 这些机制和对持续AR刺激的需求导致了 恩杂鲁胺，这是一种下一代激素疗法，可直接有效地拮抗AR，从而 延长转移性CRPC男性患者的生存期。不幸的是，Enzalutamide的反应是暂时的， 反抗最终导致死亡。因此，Enzalutamide耐药是一个主要且广泛的临床问题 治疗晚期前列腺癌 最近的证据表明，恩杂鲁胺耐药是由糖皮质激素的上调驱动的 受体（GR），其重建通常对AR刺激有反应的50%基因的表达。 不幸的是，这一发现的临床应用受到以下事实的挑战： 消融对人类是致命的。然而，确定肿瘤组织特异性机制，使GR 刺激可能会提供一个潜在的治疗目标，而不会损害患者的健康。 我们假设，AR拮抗剂抵抗时发生的GR刺激伴随着 肿瘤特异性的代谢机制，使大量的皮质醇，GR激动剂的局部浓度降低。我们 初步数据表明，11β-羟基类固醇脱氢酶-2（11β HSD 2），主要是 负责皮质醇失活，随着AR拮抗剂抵抗而丧失，导致局部皮质醇增加 浓度的此外，我们假设阻断这种代谢机制将逆转GR 刺激，从而恢复对AR拮抗剂治疗的反应性。我们的初步数据显示， 通过恢复11 β HSD 2的表达或阻断11β HSD 2的表达机制来替代11β HSD 2的酶功能， 是11β HSD 2蛋白降解所必需的，逆转代谢表型并恢复对AR的敏感性 拮抗剂治疗。在目标1中，我们将确定通过用下一种药物治疗所赋予的代谢表型。 CRPC的激素治疗。在目标2中，我们将确定调节 糖皮质激素代谢在AR拮抗剂抵抗中的作用。在目标3中，我们将确定 恢复AR拮抗剂抗性的基线代谢表型。总之，这些研究将确定 并在临床上验证驱动AR拮抗剂抗性的机制。预计这项工作将导致 确定对下一代激素疗法的耐药性的肿瘤特异性机制， 并最终开发出针对致命形式的 前列腺癌