Development of Castration Resistance by Alternative AR Splicing

通过选择性 AR 拼接开发去势抵抗力

• 批准号: 8475912
• 负责人: Stephen R. Plymate
• 金额: $ 40.65万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-24 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475912
• 关键词: Ablation; Address; Alternative Splicing; Androgen Receptor; Androgens; Appearance; Binding; Bypass; C-terminal; Castration; Cells; Cellular Stress; Cessation of life; Chromatin; Clinical; Clinical Research; Complex; DNA Sequence Rearrangement; Data; Development; Dimerization; Event; Future; Gene Activation; Gene Expression Profile; Generations; Genes; In Vitro; Instruction; Knock-out; Lead; Length; Ligand Binding Domain; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mitotic; Nuclear Translocation; Oncogenic; PC3 cell line; Patients; Proteins; RNA Splicing; Receptor Gene; Receptor Inhibition; Receptor Signaling; Recurrence; Regulation; Relapse; Resistance; Role; Site; Spliceosomes; Structure; Suggestion; Therapeutic Agents; Time; Transactivation; Transgenic Mice; Ubiquitination; Variant; Xenograft procedure; abiraterone; cancer therapy; castration resistant prostate cancer; deprivation; in vivo; inhibitor/antagonist; mRNA Precursor; mouse model; preclinical study; prostate cancer cell; protein expression; response; tumor; tumor progression; tumor xenograft

One mechanism used by prostate cancers to escape androgen deprivation and become castrate resistant prostate cancer (CRPC) is generation of splice variant(s) (ARsv) of the androgen receptor (AR) that no longer contain the C-terminal ligand-binding domain and are constitutively active. We have shown that these forms occur not simply because of castration, but also require a decrease in intratumoral androgen levels. Additionally, we have shown in preclinical studies that the newer androgen targeting agents such as abiraterone and MDV3100 are potent agents in generating ARsvs. Moreover, these constitutively active ARsvs generate a mitotic transcriptome that Is significantly altered from the canonical AR-ligand-driven transcriptome. Clinically, the appearance of the ARsvs has been associated with more rapid progression and time to death. However, the ARsv usually is co-expressed with the full-length AR (ARfl), raising the question as to whether ARfl is required for ARsv activity. It has also not been shown how the ARSV transcriptome is generated, i.e. do the ARsvs interact at different sites on chromatin the ARfl? A third issue is whether generation of ARsvs is a transcriptional event due to intragenic rearrangement of the AR gene or whether the variants can also be generated by post-transcriptional splicing mechanisms. Finally, clinical studies have not been performed that identify the clinical spectrum of ARsv presentation. These questions are important to address in order to develop appropriate therapy for the patients that invariably will relapse on even the newest prostate cancer treatments directed at AR inhibition. In this project we will address these questions by addressing the following Hypothesis and performing four specific aims: Hypothesis: Constitutively active androgen receptor splice variants (ARsv) are generated by alternative splicing of AR pre-mRNA in response to decreased intra-tumoral androgen levels as cell stress in induced; these variants maintain AR-driven tumor progression, however, the effect of the AR variant may differ depending on variant structure and whether the variant is acting independently or through dimerization with ARfi. Ultimately, the expression of ARsv will determine development of CRPC and the response to therapy.

前列腺癌用来逃避雄激素剥夺并产生去势抵抗的一种机制 前列腺癌 (CRPC) 是雄激素受体 (AR) 剪接变体 (ARsv) 的产生， 不再含有 C 端配体结合结构域并且具有组成型活性。我们已经证明这些 形式的发生不仅仅是因为去势，而且还需要瘤内雄激素水平的降低。 此外，我们在临床前研究中表明，较新的雄激素靶向药物，例如 阿比特龙和 MDV3100 是产生 ARsv 的有效药物。此外，这些构成性活性 ARsv 产生的有丝分裂转录组与典型的 AR 配体驱动的转录组相比发生了显着改变 转录组。临床上，ARsvs 的出现与更快的进展有关 和死亡时间。然而，ARsv 通常与全长 AR (ARfl) 共表达，从而提高了 关于 ARsv 活动是否需要 ARfl 的问题。也没有显示 ARSV 如何 生成转录组，即 ARsv 是否在 ARfl 染色质上的不同位点相互作用？第三个问题是 ARsvs 的产生是否是由于 AR 基因的基因内重排而导致的转录事件或 变体是否也可以通过转录后剪接机制产生。最后，临床 尚未开展研究来确定 ARsv 表现的临床谱。这些问题 重要的是要解决这些问题，以便为总是会复发的患者制定适当的治疗方法 甚至针对 AR 抑制的最新前列腺癌治疗方法。在这个项目中我们将解决这些问题 通过解决以下假设并执行四个具体目标来提出问题： 假设： 组成型活性雄激素受体剪接变体 (ARsv) 由 AR 的选择性剪接产生 mRNA前体响应细胞应激诱导的肿瘤内雄激素水平降低；这些变体 维持 AR 驱动的肿瘤进展，然而，AR 变体的效果可能因变体而异 结构以及变体是否独立发挥作用还是通过与 ARfi 的二聚化作用。最终， ARsv 的表达将决定 CRPC 的发展和对治疗的反应。