Inhibition of castration resistant prostate cancer by targeting of the IKKbeta/AR signaling

通过靶向 IKKbeta/AR 信号传导抑制去势抵抗性前列腺癌

• 批准号: 9216224
• 负责人: Hancai Dan
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9216224
• 关键词: Androgen Receptor; Androgens; Blood; CYP17A1 gene; Cancer Cell Growth; Cancer Etiology; Castration; Catalytic Domain; Cell Proliferation; Cell Survival; Cells; Cessation of life; Complex; Data; Development; Disease; FDA approved; Failure; Growth; Human; IKBKB; Impairment; In Vitro; Induction of Apoptosis; Inhibition of Cell Proliferation; Knockout Mice; LNCaP; Lead; Link; Malignant neoplasm of prostate; Mass Spectrum Analysis; Metastatic Prostate Cancer; Metastatic/Recurrent; Molecular; Mutation; Oncogenic; Operative Surgical Procedures; Organoids; PTEN gene; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Prostate Cancer therapy; Prostatectomy; Protein Kinase; Radiation; Receptor Gene; Receptor Inhibition; Receptor Signaling; Regulation; Resistance; Role; Signal Pathway; Testing; Therapeutic; Tissues; Transactivation; Treatment Efficacy; Tumor-Derived; United States; Up-Regulation; Work; Xenograft Model; Xenograft procedure; abiraterone; androgen deprivation therapy; androgen sensitive; base; cancer cell; castration resistant prostate cancer; effective therapy; efficacy testing; experimental study; improved; in vivo; inhibitor/antagonist; insight; knock-down; men; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; response; therapeutic evaluation; therapeutic target; therapy resistant; three dimensional cell culture; tumor progression

Prostate cancer (PCa) is the second leading cause of cancer-related deaths for men in the United States. Prostatectomy and radiation are standard front line therapies, but a significant portion of these patients will recur and eventually develop metastatic disease. The primary means of treatment for patients with recurrent/metastatic PCa is blockade of androgen receptor (AR) or the use of androgen- deprivation therapy (ADT) through surgical and/or pharmacological depletion of circulating androgens. Nevertheless, these types of treatment only last for 1 or 2 years. The disease will almost always recur, even with low levels of circulating androgens in the blood, and progress toward becoming a castration resistant prostate cancer (CRPC) that usually is fatal. Therapeutic failure of ADT is often accompanied by molecular alterations of the AR, including AR overexpression and mutation. In addition, the abnormal activation of other survival pathways through compensatory mechanisms following androgen depletion and AR inhibition is also essential for CRPC progression and therapeutic resistance. Through mass spectrometry analysis, we have found that IkappaB kinase beta (IKKbeta), one of the two catalytic subunits of the IKK complex that controls NF-κB activity, associates with and phosphorylates androgen receptor in CRPC cells. IKKbeta activity is significantly elevated in CRPC cells and knockdown of IKKbeta leads to a dramatic decrease in AR signaling. Furthermore, the novel IKKβ inhibitor, CmpdA, when used as either a single agent or in combination with a FDA approved AR inhibitor MDV3100, leads to a significant inhibition of CRPC cell proliferation and survival. The overall objective of this project is to determine the role of IKKβ in regulating CRPC growth and to test the therapeutic efficacy of the IKKbeta inhibitor CmpdA in CRPC. We hypothesize that IKKbeta is a critical driver for CRPC and that inhibition of IKKbeta, in combination with AR inhibitors, could lead to regression of CRPC. To test this, we will determine whether IKKbeta is required for CRPC growth in vitro and in vivo in established cells, characterize the mechanism and significance of IKKbeta regulation of AR in CRPC and determine the therapeutic potential of dual targeting of IKKbeta and AR in CRPC. Completion of this project will provide important insight into how to effectively treat CRPC through a combination of IKKbeta inhibitor and androgen blockade.

前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因 States.前列腺切除术和放射治疗是标准的一线治疗，但其中很大一部分 患者将复发并最终发展为转移性疾病。治疗的主要手段 复发性/转移性PCa患者是雄激素受体（AR）阻断或使用雄激素- 通过手术和/或药物消耗循环雄激素的剥夺疗法（ADT）。 然而，这些类型的治疗仅持续1或2年。这种疾病几乎总是会复发， 即使血液中循环的雄激素水平很低， 耐药前列腺癌（CRPC）通常是致命的。ADT治疗失败通常伴随着 通过AR的分子改变，包括AR过表达和突变。此外该 雄激素后通过代偿机制异常激活其他存活途径 消耗和AR抑制对于CRPC进展和治疗抗性也是必需的。通过 质谱分析，我们发现，IkappaB激酶β（IKK β），两个 IKK复合物的催化亚单位，控制NF-κB活性，与 CRPC细胞中的雄激素受体。IKK β活性在CRPC细胞中显著升高， IKK β的敲低导致AR信号传导的显著减少。此外，新的IKKβ 抑制剂CmpdA，当作为单一药剂或与FDA批准的AR组合使用时 抑制剂MDV 3100导致CRPC细胞增殖和存活的显著抑制。整体 本项目的目的是确定IKKβ在调节CRPC生长中的作用， IKK β抑制剂CmpdA在CRPC中的治疗功效。我们假设IKKbeta是一个关键的 CRPC驱动因子和IKK β抑制剂与AR抑制剂联合可能导致 CRPC的回归为了验证这一点，我们将确定IKK β是否是CRPC生长所必需的， 在体外和体内建立的细胞中，表征IKK β调节的机制和意义 CRPC中AR的表达，并确定CRPC中IKK β和AR双重靶向的治疗潜力。 该项目的完成将提供重要的见解，如何有效地治疗CRPC通过 IKK β抑制剂和雄激素阻断剂的组合。