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: 10058257
• 负责人: Nima Sharifi
• 金额: $ 36.83万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058257
• 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; Lead; Ligands; Malignant neoplasm of prostate; Mediating; Medical Castration; Metabolic; Metabolism; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Oxidoreductase; Pathway interactions; Patients; Pharmacology; Proteins; Receptor Up-Regulation; Resistance; Stanolone; Testosterone; Therapeutic; Therapeutic Effect; Tumor Tissue; United States; Up-Regulation; Work; advanced prostate cancer; androgen deprivation therapy; androgen sensitive; castration resistant prostate cancer; clinical application; cofactor; enzyme activity; glucocorticoid receptor alpha; hormone therapy; improved; inorganic phosphate; insight; men; metabolic phenotype; new therapeutic target; next generation; protein degradation; protein expression; 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 前列腺癌取决于雄激素和雄激素受体（AR）的生长和进展。 通常最初通过医学或手术治疗雄激素剥夺疗法 cast割；但是，肿瘤有时会作为耐castration的前列腺癌（CRPC）复发，该癌症的发展 到肿瘤内产生睾丸激素和/或二氢睾丸激素和AR刺激。标识 这些机制以及对持续AR模拟的要求导致了 enzalutamide，这是一种下一代激素疗法，直接并潜在地拮抗AR，从而 扩展转移性CRPC男性的生存。不幸的是，对enzalutamide的反应是暂时的， 抵抗最终导致死亡。因此 对于晚期前列腺癌患者。 最近的证据表明，埃纳扎拉胺的耐药性是由糖皮质激素的上调驱动的 受体（GR）重新建立了通常对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是由完整且全身性GR的事实挑战 在人类中消融是致命的。但是，鉴定肿瘤组织特异性机制可以使GR 刺激可能会提供潜在的治疗靶标，不会损害患者。 我们假设AR拮抗剂抗性发生的GR刺激是由A实现的 肿瘤特异性的代谢机制，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-羟基固醇脱氢酶2（11βHSD2），这是主要的酶 负责皮质醇灭活的负责，由于AR拮抗剂的抗性而丢失，导致局部皮质醇增强 浓度。此外，我们假设阻止这种代谢机制将逆转GR 刺激，从而恢复对AR拮抗剂疗法的反应性。我们的初步数据表明 通过恢复11βHSD2表达或阻止机械来替换11βHSD2酶函数 是11βHSD2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AIM 1中，我们将确定由接下来处理的代谢表型 CRPC的生成激素疗法。在AIM 2中，我们将确定调节的分子机制 AR拮抗剂耐药性中的糖皮质激素代谢。在AIM 3中，我们将确定治疗意义 恢复AR拮抗剂抗性中基线代谢表型的方法。这些研究将共同​​确定 并在临床上验证驱动AR拮抗剂抗性的机制。预计这项工作将领导 确定对下一代激素疗法抗性的肿瘤特异性机制 具有药理目标的目标，并为致命形式的新治疗策略的事件制定 前列腺癌。