Natural Product Screening for Prostate Cancer Therapeutics Using Gene Expression

描述(申请人提供)：在第一阶段，将测试新获得的天然产品提取物，以寻找专门针对前列腺癌复发患者雄激素受体刺激生长途径的关键基因的化合物。这一点很重要，因为雄激素受体途径被解除调控，对复发的转移性前列腺癌至关重要，即使在没有雄激素的情况下也是如此。有趣的是，复发性肿瘤是雄激素非依赖性的，但雄激素受体途径通过各种分子机制重新获得关键的积极调节作用。一种定量的高通量基因芯片分析Arrayplate将测试将受雄激素依赖的前列腺癌细胞的雄激素激活影响的30个基因的基因表达模式逆转为非活动状态的产品。这些提取物来自亚利桑那大学西南天然产品研究和商业化中心最近发现的索诺兰沙漠植物和相关微生物。第二阶段将在第一阶段确定的再次确认的命中部分的基础上进行进一步分离和重新测试，以尝试分离和鉴定活性化合物，具有足够活性的化合物将在不同种类的雄激素非依赖性复发性前列腺癌细胞上进行体外和体内测试。针对复发肿瘤获得雄激素非依赖性的各种机制，但保持对雄激素受体激活途径的依赖的新疗法将对复发的激素不敏感的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延长，前列腺癌正迅速成为老年男性最常见的实体癌症，并成为男性第二大癌症杀手。大多数患者死于激素耐药的前列腺癌，因为目前还没有替代疗法可用于治疗激素耐药的转移性前列腺癌。从天然产品中发现新的治疗方法具有巨大的潜力。这笔赠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未开发来源。

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.