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. ? ? ?
| Xu, Ya-Ming; Liu, Manping X; Grunow, Nathan et al. (2015) Discovery of Potent 17?-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors. J Med Chem 58:6984-93 |
