Natural Product Screening for Prostate Cancer Therapeutics Using Gene Expression

描述（由申请人提供）：在I期，将测试新获得的天然产品提取物，以寻找特异性靶向基因的化合物，这些基因对复发性前列腺癌的生长刺激的雄激素受体通路至关重要。这很重要，因为雄激素受体通路不受调节，即使在缺乏雄激素的情况下，对复发性转移性前列腺癌也是至关重要的。有趣的是，复发性肿瘤是雄激素独立的，但雄激素受体途径通过各种分子机制恢复了关键的活跃调节作用。一种定量的高通量基因芯片试验ArrayPlate将测试能够逆转受雄激素依赖性前列腺癌细胞雄激素激活影响的30个基因的基因表达模式到失活状态的产品。这些提取物是从索诺兰沙漠植物和相关微生物中提取的，这些微生物是最近由亚利桑那大学的西南天然产物研究和商业化中心发现的。第二阶段将继续对第一阶段中鉴定的再次确认的hit分数进行进一步的分离和用相同的方法重新测试，以试图分离和鉴定活性化合物，具有足够活性的化合物将在体外和体内对不同类型的雄激素不依赖型复发性前列腺癌细胞进行测试。针对复发性肿瘤获得雄激素独立性的各种机制，但仍依赖于雄激素受体激活途径的新疗法将对复发性激素难治性前列腺癌患者产生重大治疗影响。由于早期发现和预期寿命的延长，前列腺癌正迅速成为老年男性中最常见的实体癌，也是男性的第二大癌症杀手。大多数患者死于激素难治性前列腺癌，因为目前没有替代疗法可用于治疗激素难治性转移性前列腺癌。从天然产物中发现新的治疗方法有很大的潜力。这项拨款中使用的天然产品来自西南部，可能是前列腺癌新疗法的一个尚未开发的来源。

DESCRIPTION (provided by applicant): In Phase I, newly available natural product extracts will be tested to find compounds that specifically target genes that are critical for the androgen receptor pathway of growth stimulation in recurrent prostate cancers. This is important because the androgen receptor pathway is deregulated and critical to recurrent metastatic prostate cancer, even in the absence of androgen. Interestingly recurrent tumors are androgen independent, but the androgen receptor pathway regains a critically active regulatory role through various molecular mechanisms. A quantitative high-throughput gene chip assay, ArrayPlate, will test for products that reverse the gene expression pattern for 30 genes affected by androgen activation of androgen dependent prostate cancer cells to the inactive state. The extracts are derived from Sonoran desert plants and associated microorganisms recently discovered by the Southwest Center for Natural Product Research and Commercialization, at the University of Arizona. Phase II will follow up on reconfirmed hit fractions identified in Phase I. Fractions will be further fractionated and retested with the same assay to attempt to isolate and identify the active compounds, and compounds with sufficient activity will be tested in vitro and in vivo on different kinds of androgen independent recurrent prostate cancer cells. Novel therapeutics that target the various mechanisms by which recurrent tumors have acquired androgen independence, but maintained dependence upon the androgen receptor activation pathway will have a major therapeutic impact for patients with recurrent, hormone-refractory prostate cancer. Due to earlier detection and increased life expectancy prostate cancer is rapidly becoming the most frequent solid cancer in older men and the second leading cancer killer of men. The majority of patients die from PCa as a result of hormone-refractory disease, since no alternative therapy is currently available to treat hormone-refractory, metastatic PCa. There is great potential for the discovery of novel therapeutics from natural products. The natural products used in this grant are from the southwest and may be an untapped source of novel therapies for prostate cancer.