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.

项目摘要 靶向雄激素受体（AR）是转移性前列腺癌治疗的主要手段。通常 涉及预防睾丸雄激素合成的LHRH激动剂，或者AR拮抗剂，例如 Bicalutamide（Casodex），阻断AR转录活性。尽管对这些疗法的初步反应 有效，它们不可避免地会失败，因为耐castration的前列腺癌细胞随着AR增强而出现 活动。因此，castration抗性的前列腺癌保持其对雄激素信号的依赖。这 促使新一代的抗雄激素的发展，例如enzalutamide，它阻止了AR 通过抑制AR转移到细胞核中的作用。虽然enzalutamide代表了 治疗转移性前列腺癌，最初反应的患者最终获得了抗药性。鉴于 enzalutamide抗性的一种机制取决于糖皮质激素受体（GR）的能力 为了使AR激活一组相似的靶基因，需要阻塞GR活性 某些enzalutamide耐药性。我们先前已经确定了一组23个细胞因子，以减少 耗尽时GR依赖性转录激活。我们假设这些因素决定了GR 耐恩扎拉酰胺耐药的前列腺癌细胞中基因靶标的特异性。我们进一步提出了目标 这些因素将阻止GR驱动的耐恩扎拉酰胺耐药性前列腺癌的增殖。我们的具体 目的是1）定义这些GR辅助因子对表达GR的耐恩扎拉胺耐药前列腺的影响 癌细胞和2）确定GR辅助因子抑制enzalutamide耐药性肿瘤的能力 体内异种移植生长。这些目标的成功完成将确定GR转录的关键调节器 和耐恩扎拉胺的前列腺癌的增殖。