Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

异常的肿瘤代谢导致 AR 拮抗剂对前列腺癌产生耐药性

• 批准号: 10847199
• 负责人: Nima Sharifi
• 金额: $ 27.41万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10847199
• 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.

项目概要 前列腺癌的生长和进展依赖于雄激素和雄激素受体 (AR)。 转移性肿瘤通常首先通过药物或手术的方式进行雄激素剥夺治疗 阉割；然而，肿瘤最终会复发为去势抵抗性前列腺癌（CRPC），其进展是由于 睾酮和/或二氢睾酮的瘤内生成以及 AR 刺激。鉴定 这些机制和持续 AR 刺激的需求导致了 enzalutamide，这是一种下一代激素疗法，可直接有效地拮抗 AR，从而 延长患有转移性 CRPC 的男性的生存期。不幸的是，对恩杂鲁胺的反应是暂时的并且 反抗最终导致死亡。因此，恩杂鲁胺耐药性是一个主要且普遍的临床问题 对于晚期前列腺癌患者。 最近的证据表明，恩杂鲁胺耐药性是由糖皮质激素的上调驱动的 受体 (GR)，它会重新建立 50% 通常对 AR 刺激有反应的基因的表达。 不幸的是，这一发现的临床应用受到以下事实的挑战：完全且系统的 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 刺激可能提供一个不会危及患者健康的潜在治疗目标。 我们假设伴随 AR 拮抗剂抵抗而发生的 GR 刺激伴随着 肿瘤特异性代谢机制，可提供丰富的局部皮质醇浓度（一种 GR 激动剂）。我们的 初步数据表明，11β-羟基类固醇脱氢酶-2 (11βHSD2)，该酶主要是 负责皮质醇失活，随着 AR 拮抗剂抵抗而丢失，导致局部皮质醇增强 浓度。此外，我们假设阻断这种代谢机制会逆转 GR 刺激，从而恢复对 AR 拮抗剂治疗的反应。我们的初步数据表明 通过恢复 11βHSD2 表达或阻断机制来取代 11βHSD2 酶功能 是 11βHSD2 蛋白降解所必需的，可逆转代谢表型并恢复对 AR 的敏感性 拮抗剂疗法。在目标 1 中，我们将确定接下来的治疗所赋予的代谢表型—— 针对 CRPC 的新一代激素疗法。在目标 2 中，我们将确定调节的分子机制 AR拮抗剂抵抗中的糖皮质激素代谢。在目标 3 中，我们将确定治疗意义 恢复 AR 拮抗剂耐药性的基线代谢表型。这些研究将共同​​确定 并临床验证驱动 AR 拮抗剂耐药的机制。预计这项工作将导致 识别肿瘤特异性的下一代激素疗法耐药机制 药理学上具有针对性，并最终开发针对致命形式的新治疗策略 前列腺癌。