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

基本信息

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
项目类别：
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

项目摘要

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然而，肿瘤最终会复发，成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。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，恩杂鲁胺的反应是暂时的并且是暂时的。因此，耐药性最终导致死亡。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 然而，消融对人类来说是致命的，然而，确定了一种能够实现 GR 的肿瘤组织特异性机制。刺激可能提供一个不会危及患者健康的潜在治疗目标。我们发现，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）。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此外，我们还发现阻断这种代谢机制可以逆转 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 的敏感性在目标 1 中，我们将确定接下来的治疗所赋予的代谢表型。在目标 2 中，我们将确定调节 CRPC 的分子机制。 AR 拮抗剂耐药中的糖皮质激素代谢在目标 3 中，我们将确定其治疗意义。这些研究将共同确定恢复 AR 拮抗剂耐药性的基线代谢表型的方法。并在临床上验证 AR 拮抗剂耐药性的机制，预计这项工作将取得进展。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。