Targeting the glucocorticoid receptor 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 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），其阻断AR转录活性。虽然这些疗法的最初反应 有效，但它们不可避免地失败，因为去势抵抗性前列腺癌细胞出现增强的AR 活动因此，去势抵抗性前列腺癌维持其对雄激素信号传导的依赖。这 这促使了新一代抗雄激素药物的开发，如恩杂鲁胺，它可以阻断AR 通过抑制AR易位到细胞核中发挥作用。虽然Enzalutamide代表了 在转移性前列腺癌的治疗中，最初有反应的患者最终获得耐药性。鉴于 恩杂鲁胺耐药的一种机制依赖于糖皮质激素受体（GR）替代 为了使AR激活增殖所必需的一组类似的靶基因，阻断GR活性可能会对抗 某些enzalutamide耐药病例。我们以前已经确定了一组23个细胞因子， GR依赖性转录激活时耗尽。我们假设这些因素决定了GR 恩杂鲁胺耐药前列腺癌细胞基因靶点特异性。我们进一步建议， 这些因子将阻断GR驱动的恩杂鲁胺抗性前列腺癌的增殖。我们的具体 目的是：1）确定这些GR辅因子对表达GR的Enzalutamide耐药前列腺的影响， 癌细胞和2）确定GR辅因子抑制恩杂鲁胺耐药肿瘤的能力 体内异种移植物生长。这些目标的成功完成将确定GR转录的关键调控因子 和增殖。

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.