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)是治疗转移性前列腺癌的主要方法。这通常是 涉及阻止睾丸雄激素合成的LHRH激动剂或AR拮抗剂，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 是有效的，但不可避免地会失败，因为耐阉割的前列腺癌细胞出现了增强的AR 活动。因此，对去势耐受的前列腺癌维持对雄激素信号的依赖。这 促进了新一代抗雄激素药物的开发，如阻断AR的苯扎鲁胺 通过抑制AR移位到核内而起作用。尽管苯扎鲁胺代表着在 对于转移性前列腺癌的治疗，患者最初有反应，最终获得抗药性。考虑到 苯扎鲁胺耐药的一个机制依赖于糖皮质激素受体(GR)的替代能力 对于AR来说，激活一组类似的增殖所必需的靶基因，阻断GR活性可能会 某些对苯扎鲁胺耐药的病例。我们之前已经确定了一组23种细胞因子，它们可以减少 耗尽时依赖GR的转录激活。我们假设这些因素决定了GR 对苯扎鲁胺耐药的前列腺癌细胞的基因靶点的特异性。我们进一步建议将目标定为 这些因素将阻止GR驱动的、苯扎鲁胺耐药的前列腺癌的增殖。我们的特定 目的是1)明确这些GR辅助因子对GR表达的、苯扎鲁胺耐药的前列腺的影响 以及2)确定GR辅助因子抑制耐药肿瘤的能力 异种移植瘤体内生长。成功完成这些目标将确定GR转录的关键调控因素 以及对苯扎鲁胺耐药的前列腺癌的增殖。