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.

前列腺癌逃避雄激素剥夺并产生去势抵抗力的一种机制 前列腺癌(CRPC)是雄激素受体(AR)的剪接变异体(S)(ARsv)的产物 不再含有C末端的配基结合域，并且具有结构性活性。我们已经证明，这些 这种形式的发生不仅仅是因为去势，还需要降低肿瘤内的雄激素水平。 此外，我们在临床前研究中表明，较新的雄激素靶向药物，如 阿比特龙和MDV3100是产生ARS的有效药物。此外，这些结构性的活跃 ARsv产生一个有丝分裂转录组，该转录组与典型的AR配体驱动的转录组相比发生了显著变化 转录组。临床上，急性呼吸窘迫综合征的出现与病情进展更快有关。 和死亡的时间。然而，ARsv通常与全长AR(ARf1)共表达，从而提高了 关于ARSF活动是否需要ARFL的问题。它也没有展示ARSV是如何 转录组的产生，即ARsv是否在染色质上的不同位置相互作用？第三个问题是 ARsv的产生是由于AR基因的基因内重排还是基因内重排导致的转录事件 变异体是否也可以由转录后剪接机制产生。最后，临床 目前还没有研究确定ARsv的临床表现谱。这些问题 都是需要解决的重要问题，以便为总是会复发的患者开发适当的治疗方法 甚至是针对AR抑制的最新前列腺癌治疗方法。在本项目中，我们将解决这些问题 通过回答以下假设并实现四个具体目标来提出问题：假设： 结构性活性雄激素受体剪接变异体(ARsv)是通过AR的选择性剪接产生的 Pre-mRNA对肿瘤内雄激素水平降低的反应，因为细胞应激诱导；这些变体 维持AR驱动的肿瘤进展，然而，AR变异体的效果可能因变异体而异 结构，以及该变异体是独立作用还是通过与arfi的二聚化作用。归根结底， ARsv的表达将决定CRPC的发展和对治疗的反应。