Targeting Androgen Receptor Activity in Prostate Cancer

描述（由申请人提供）：前列腺癌（PCa）是美国男性死亡的第二大原因。前列腺癌最初是雄激素依赖性（AD），抗雄激素治疗对几乎所有患者都有效。不幸的是，患者发展并最终死于雄激素非依赖性疾病，此时前列腺癌肿瘤继续生长和转移，尽管雄激素水平被阉割。越来越多的证据表明，Al - PCa的持续生长依赖于雄激素受体（AR）的持续表达和激活。由于AR的主要功能是作为一种转录因子，与抑制凋亡和促进增殖的靶基因中的雄激素反应元件（ARE）结合，我们假设抑制AR的转录活性将导致Al PCa的生长减少。我们的总体目标是通过阻断AR- are相互作用来抑制AR转录活性，从而在体外和体内延缓人类Al - PCa的生长。这一证据将为未来通过干扰AR- are相互作用来鉴定AR转录活性的小分子抑制剂的研究奠定基础。因此，我们的长期目标是开发一种特异性阻断AR转录活性的药物，这种药物可能用于治疗Al前列腺癌患者。对于目前的应用，我们阻断AR与其同源ARE结合的主要策略涉及AR的缺失突变体的异位表达，该突变体包含AR DNA结合域（DBD），但缺乏反活化域（TAD）和配体结合域（LBD）。我们和其他人已经证明AR- dbd构建物已经被证明可以抑制全长AR的转录活性。使用这种策略，我们提出了以下具体目标：1)建立AR- dbd的表达通过阻止AR- are相互作用来抑制AR的转录活性，2)证明抑制AR- are相互作用导致体外和体内Al PCa的生长减少。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the second leading cause of mortality amongst U.S. men. PCa is initially androgen-dependent (AD) and anti-androgen therapy is effective in virtually all patients. Unfortunately, patients develop and eventually succumb to androgen-independent disease, at which point PCa tumors continue to grow and metastasize despite castrate levels of androgen. A growing body of evidence has established that sustained growth of Al PCa is dependent upon continued expression and activation of the androgen receptor (AR). Because the primary function of the AR is to serve as a transcription factor that binds to the androgen response element (ARE) in target genes that inhibit apoptosis and promote proliferation, we hypothesize that inhibition of the transcriptional activity of the AR will result in diminished growth of Al PCa. Our overall objective is to provide proof-of-principle evidence that inhibition of AR transcriptional activity by blocking the AR-ARE interaction will retard human Al PCa growth in vitro and in vivo. This evidence will be the basis for future studies to identify small molecule inhibitors of AR transcriptional activity by interfering with the AR-ARE interaction. Thus, our long-term objective is to develop a drug to specifically block AR transcriptional activity that could potentially be used to treat patients with Al prostate cancer. For the current application, our principal strategy to block binding of the AR to its cognate ARE involves the ectopic expression of a deletion mutant of the AR, which contains the AR DNA binding domain (DBD), but lacks both the transactivation domain (TAD) and ligand binding domain (LBD). We and others have shown that AR-DBD constructs have been shown to inhibit the transcriptional activity of the full-length AR. Using this strategy, we propose the following specific aims: 1) Establish that expression of the AR-DBD inhibits the transcriptional activity of the AR by preventing the AR-ARE interaction, and 2) Demonstrate that inhibition of the AR-ARE interaction results in reduced growth of Al PCa both in vitro and in vivo.