The Androgen Receptor in Hormone Refractory Disease

激素难治性疾病中的雄激素受体

• 批准号: 7669225
• 负责人: MYLES A BROWN
• 金额: $ 22.4万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-19 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7669225
• 关键词: Androgen Metabolism; Androgen Receptor; Androgen Therapy; Androgens; Back; Biological Assay; Bone Marrow; CDC2 Protein Kinase; Castration; Cell Line; Chromosomes, Human, Pair 21; Clinic; Clinical; Clinical Trials; Data; Data Set; Drug Delivery Systems; Dutasteride; Effectiveness; Enzymes; Event; Future; Gene Expression; Gene Expression Profile; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; Hormones; Hydrocortisone; Laboratories; Lasers; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Messenger RNA; Methods; Molecular; Neoplasm Metastasis; Oligonucleotide Microarrays; Organ; PC3 cell line; Patients; Pattern; Phase II Clinical Trials; Phosphotransferases; Play; Production; Prostate-Specific Antigen; Proteins; Refractory; Refractory Disease; Relapse; Reporting; Reproduction spores; Research Personnel; Role; Sampling; Series; Site; Specimen; Standards of Weights and Measures; Stanolone; TMPRSS2 gene; Testing; Testosterone; Translating; Translations; Validation; Xenograft procedure; androgen independent prostate cancer; cancer cell; concept; deprivation; fusion gene; inhibitor/antagonist; novel therapeutics; programs; receptor expression; receptor function; small hairpin RNA; therapeutic target; transcription factor; tumor; tumor growth; tumor progression

The vast majority of prostate cancers are androgen dependent, and androgen deprivation therapy (ADT) remains the standard treatment for non-organ-confined prostate cancer. Unfortunately, patients treated with ADT invariably relapse with progressive systemic prostate cancer that has been termed hormone-refractory or androgen-independent prostate cancer (AlCaP). Significantly, most cases of AlCaP are associated with high levels of androgen receptor (AR) mRNA and protein, as well as renewed expression of androgen regulated genes (such as prostate specific antigen (PSA), TMPRSS2, and the recently identified TMPRSS2/ETS fusion genes), suggesting that AR and AR-regulated genes remain critical for tumor growth in AlCaP. However, the molecular events mediating the apparent reactivation of AR transcriptional activity in AlCaP, and the critical downstream AR-regulated genes, remain to be determined. We recently reported our results using Affymetrix oligonucleotide microarrays to compare gene expression in a series of laser capture microdissected primary prostate cancer samples versus AlCaP bone marrow metastases. These studies demonstrated a high level of expression of AR mRNA in AlCaP together with renewed expression of multiple strongly AR-regulated genes, confirming substantial reactivation of AR-mediated transcription despite castrate androgen levels. With respect to potential mechanisms for this AR reactivation, we found that AlCaP samples had marked increases in enzymes that mediate androgen metabolism, suggesting that enhanced synthesis of the ligands testosterone and dihydrotestosterone (DHT) by AlCaP is one potential mechanism contributing to relapse after castration. The Specific Aims of this Project are to: Aim 1: Complete the current trial of ketoconozole, hydrocortisone, and dutasteride, and initiate new phase II clinical trials of compounds that suppress AR expression or function in androgen-independent Prostate cancer. Aim 2: Combine gene expression data from androgen-independent prostate cancer cell lines and xenografts with AR ChlP-on-chip from these cell lines to identify critical AR cooperating factors and regulated genes that may be therapeutic targets in androgen independent prostate cancer. Aim 3: Validate AR-regulated genes as therapeutic targets in clinical AlCaP cancer.

绝大多数前列腺癌是雄激素依赖性的，雄激素剥夺治疗（ADT） 仍然是非器官局限性前列腺癌的标准治疗方法。不幸的是， ADT总是复发，伴有进行性系统性前列腺癌，被称为难治性前列腺癌 或雄激素非依赖性前列腺癌（AlCaP）。值得注意的是，大多数AlCaP病例与 高水平的雄激素受体（AR）mRNA和蛋白，以及雄激素的重新表达 调节基因（如前列腺特异性抗原（PSA），TMPRSS 2，和最近发现的 TMPRSS 2/ETS融合基因），表明AR和AR调节基因对肿瘤生长仍然至关重要 在AlCaP。然而，介导AR转录活性表观再活化的分子事件在细胞中并不存在。 AlCaP和关键的下游AR调节基因仍有待确定。我们最近报道了我们的 结果使用Affyssin寡核苷酸微阵列比较一系列激光捕获中的基因表达 显微切割的原发性前列腺癌样品与AlCaP骨髓转移。这些研究 证明了在AlCaP中AR mRNA的高水平表达以及多个 强AR调节基因，证实了AR介导的转录的实质性再激活，尽管 阉割雄激素水平关于这种AR再激活的潜在机制，我们发现AlCaP 样本中介导雄激素代谢的酶显著增加，这表明增强的 通过AlCaP合成配体睾酮和二氢睾酮（DHT）是一种潜在的机制 导致阉割后复发。 该项目的具体目标是： 目标1：完成当前的酮康唑、氢化可的松和度他雄胺试验，并启动新的II期临床试验 在雄激素非依赖性前列腺中抑制AR表达或功能的化合物的临床试验 癌 目的2：联合收割机结合雄激素非依赖性前列腺癌细胞系和异种移植物的基因表达数据 用来自这些细胞系的AR ChIP芯片来鉴定关键的AR协同因子和调节基因， 可能是雄激素非依赖性前列腺癌的治疗靶点。 目的3：将转录调控基因作为临床AlCaP肿瘤治疗的靶点。