Targeting the glucocorticoid receptor in enzalutamide resistant prostate cancer

靶向恩杂鲁胺耐药性前列腺癌中的糖皮质激素受体

• 批准号: 9178221
• 负责人: Michael J. Garabedian
• 金额: $ 18.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178221
• 关键词: Addison' s disease; Adverse effects; Affect; Agonist; Androgen Antagonists; Androgen Receptor; Androgens; Apoptosis; Bicalutamide; Binding; Binding Sites; Cancer Patient; Cell Nucleus; Cell Proliferation; Cells; ChIP-seq; Clinical; Development; Disease Resistance; Drug Targeting; Drug resistance; Exhibits; Gene Targeting; Generations; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; HDAC5 gene; Human; LNCaP; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Neoplasm Circulating Cells; Ornithine Decarboxylase; Pathway interactions; Patients; Pattern; Proliferation Marker; Prostate; Publishing; RNA Interference; RNA interference screen; Receptor Gene; Receptor Signaling; Receptor Up-Regulation; Regulation; Repression; Resistance; STK6 gene; Signal Transduction; Specificity; Staging; Testing; Therapeutic; Transcriptional Activation; VCaP; Xenograft procedure; alternative treatment; castration resistant prostate cancer; cell growth; cell type; cofactor; combat; effective therapy; genome-wide; in vivo; inhibitor/antagonist; knock-down; men; next generation; novel; overexpression; prevent; prostate cancer cell; prostate cancer model; receptor; receptor binding; receptor expression; receptor function; response; restoration; small hairpin RNA; success; therapeutic target; tumor; tumor growth; tumor xenograft

Project Summary Targeting the androgen receptor (AR) is the mainstay of treatment for metastatic prostate cancer. This usually involves either LHRH agonists that prevent testicular androgen synthesis or AR antagonists, such as bicalutamide (Casodex), which block AR transcriptional activity. Although initial responses to these therapies are effective, they inevitably fail because castration-resistant prostate cancer cells emerge with enhanced AR activity. Thus, castration-resistant prostate cancers maintain their reliance on androgen signaling. This prompted the development of a new generation of anti-androgens, such as enzalutamide, which blocks AR action by inhibiting translocation of AR into the nucleus. Although enzalutamide represents a breakthrough in treatment of metastatic prostate cancer, patients who initially respond eventually acquire resistance. Given that one mechanism of enzalutamide resistance relies on the ability of the glucocorticoid receptor (GR) to substitute for AR to activate a similar set of target genes necessary for proliferation, blocking GR activity might combat certain cases of enzalutamide resistance. We have previously identified a set of 23 cellular factors that reduce GR-dependent transcriptional activation when depleted. We hypothesize that these factors dictate GR specificity at gene targets in enzalutamide-resistant prostate cancer cells. We further propose that targeting these factors would block the proliferation of GR-driven, enzalutamide-resistant prostate cancer. Our specific aims are 1) to define the impact of these GR cofactors on GR-expressing, enzalutamide-resistant prostate cancer cells and 2) to determine the capacity of the GR cofactors to inhibit enzalutamide-resistant tumor xenograft growth in vivo. Successful completion of these aims will identify key regulators of GR transcription and proliferation in enzalutamide-resistant prostate cancer.

项目概要 靶向雄激素受体（AR）是转移性前列腺癌的主要治疗方法。这通常 涉及阻止睾丸雄激素合成的 LHRH 激动剂或 AR 拮抗剂，例如 比卡鲁胺 (Casodex)，可阻断 AR 转录活性。尽管对这些疗法的初步反应 虽然有效，但不可避免地会失败，因为去势抵抗性前列腺癌细胞的 AR 增强 活动。因此，去势抵抗性前列腺癌维持对雄激素信号传导的依赖。这 促进了新一代抗雄激素的开发，例如恩杂鲁胺，它可以阻断 AR 通过抑制 AR 转位到细胞核中发挥作用。尽管恩杂鲁胺代表了一项突破 在转移性前列腺癌的治疗中，最初有反应的患者最终会产生耐药性。鉴于 恩杂鲁胺耐药的一种机制依赖于糖皮质激素受体 (GR) 的替代能力 为了让 AR 激活增殖所需的一组相似的靶基因，阻断 GR 活性可能会对抗 恩杂鲁胺耐药的某些病例。我们之前已经确定了一组 23 种细胞因子，可减少 当 GR 耗尽时，转录激活依赖于 GR。我们假设这些因素决定了 GR 恩杂鲁胺耐药性前列腺癌细胞中基因靶标的特异性。我们进一步建议，瞄准 这些因素将阻止 GR 驱动的恩杂鲁胺耐药性前列腺癌的增殖。我们的具体 目的是 1) 确定这些 GR 辅因子对表达 GR 的恩杂鲁胺耐药前列腺的影响 癌细胞和 2) 确定 GR 辅助因子抑制恩杂鲁胺耐药肿瘤的能力 体内异种移植物生长。成功完成这些目标将确定 GR 转录的关键调节因子 和恩杂鲁胺耐药性前列腺癌的增殖。