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

前列腺癌是美国男性癌症相关死亡的第二大原因 各州。前列腺切除术和放射治疗是标准的一线治疗方法，但其中很大一部分 患者会复发，并最终发展为转移性疾病。本病的主要治疗手段是 复发/转移性前列腺癌患者雄激素受体(AR)的阻断或雄激素的使用- 剥夺疗法(ADT)通过手术和/或药物消耗循环中的雄激素。 然而，这些类型的治疗只持续一到两年。这种疾病几乎总是会复发， 即使血液中循环中的雄激素水平很低，并朝着阉割的方向发展 耐药前列腺癌(CRPC)，通常是致命的。ADT治疗失败常伴发 通过AR的分子改变，包括AR的过度表达和突变。此外， 雄激素后通过代偿机制异常激活其他生存途径 耗竭和AR抑制也是CRPC进展和治疗耐药的关键。穿过 通过质谱分析，我们发现了IkappaB激酶β(IKKbeta)，两者之一 IKK复合体的催化亚基，控制核因子-κB的活性，与之结合并磷酸化 CRPC细胞中的雄激素受体。在CRPC细胞中IKKβ活性显著升高，并且 IKKβ基因敲除导致AR信号的急剧减少。此外，小说IKKβ 单独使用或与FDA批准的AR联合使用时的抑制剂CmpdA 抑制剂MDV3100可显著抑制CRPC细胞的增殖和存活。整体而言 本项目的目的是确定IKKβ在调节CRPC生长中的作用，并测试 IKKβ抑制剂CmpdA治疗慢性前列腺癌的疗效我们假设IKKbeta是一个关键的 CRPC驱动因素和抑制IKKbeta与AR抑制剂结合可能导致 CRPC的回归。为了测试这一点，我们将确定CRPC的增长是否需要IKKbeta 在体外和体内已建立的细胞中，表征IKKβ调节的机制和意义 并确定在CRPC中双靶向IKKβ和AR的治疗潜力。 该项目的完成将为如何通过 IKKβ抑制剂和雄激素阻断的联合应用。

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.