Development of Castration Resistance by Alternative AR Splicing

前列腺癌逃避雄激素剥夺并成为去势抵抗的一种机制 前列腺癌（CRPC）是雄激素受体（AR）的剪接变体（ARsv）的产生， 更长的含有C-末端配体结合结构域，并且具有组成型活性。我们已经证明， 形式的发生不仅是因为去势，而且还需要肿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，如 阿比特龙和MDV 3100是产生ARsv的有效药物。此外，这些活性成分 ARsvs产生有丝分裂转录组，其与典型的AR配体驱动的有丝分裂转录组相比发生了显著改变。 转录组临床上，ARsvs的出现与更快的进展相关 和死亡时间然而，ARsv通常与全长AR（ARfl）共表达，从而提高了ARsv的表达。 关于ARsv活性是否需要ARfl的问题。也没有显示ARSV如何 产生转录组，即ARsvs是否在染色质上的不同位点与ARfl相互作用？第三个问题是 ARsvs的产生是否是由于AR基因的基因内重排引起的转录事件， 这些变体是否也可以通过转录后剪接机制产生。最后，临床 尚未进行确定ARsv表现的临床谱的研究。这些问题 为了为那些总是会复发的患者制定适当的治疗方法， 甚至是最新的针对AR抑制的前列腺癌治疗方法。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解决问题：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 前体mRNA对肿瘤内雄激素水平降低的反应，作为诱导的细胞应激;这些变体 维持AR驱动的肿瘤进展，然而，AR变体的作用可能因变体而异。 结构以及变体是否独立地或通过与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。

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.