Anticancer Leads from Marine Sponges and Marine Fungi

截至2004年，FDA批准的129多种小分子药物可用于延长至少13种致命癌症的预期寿命。然而，根据最近的癌症统计数据，预计2004年将有1,368,030例新的癌症病例，预计将有超过563,700名美国人死于这种疾病。癌症的治疗需要额外的治疗干预。该项目使用基于靶点的分析来发现与治疗四种最常见的实体肿瘤相关的化合物，如结肠癌/直肠癌、肺癌、乳腺癌和前列腺癌，这四种癌症加起来几乎占到70%。 NCDDG的Crews部分将探索从收集的海绵和培养的真菌库中获得的天然产品，这些海绵和培养的真菌来自三个来源：海绵、其周围的水柱和深水沉积物。将启动一项协同调查，利用四个额外的LAB NCDDG项目的优势，以追求以下九个具体目标。(1)继续在我们的资源库中研究印度-太平洋海绵和提取物作为新的抗癌先导化合物的来源的新的生物活性小分子(Mw 400-2000)。(2)收集未开发的海绵作为额外小分子的来源。(3)建立以海绵为原料的海水培养菌库； 它们周围的水柱。(4)建立深水海水养殖真菌文库。(5)利用NIBRI的表观遗传学和基于分子靶标的分析方法，继续研究当前和未来的活性提取物。(6)缩短从发现活性提取物到确定其活性成分的时间，方法是创建高通量筛选(HTS)引导分离的峰值文库，然后进行最先进的去碱基或结构阐明。(7)利用质谱学方法进行数据库挖掘和代谢组学研究，以扩大结构先导化合物的化学多样性。(八)搞引领性优化。(九)取得重要新活性化合物专利覆盖率。

As of 2004, there are more than 129 FDA approved small molecule drugs available for extending life expectancy in at least thirteen types of fatal cancers. However, based on the recent cancer statistics it is projected for 2004 that there will be 1,368,030 new cancer'cases and over 563,700 Americans are expected to succumb to this disease. Additional therapeutic interventions are needed for the treatment of cancer. This project uses target-based assays to discover compounds that will be relevant to treat the four most common solid tumor cancers such as colon/rectal, lung, breast and prostate, which together account for almost 70% of all cancer deaths in the U.S. The Crews component of the NCDDG will explore the natural products from a library of collected sponges and cultured fungi obtained from three sources: sponges, their surrounding water column, and deepwater sediments. A synergist investigation, capitalizing on the strengths of the four additional lab NCDDG programs, will be launched in pursuit of nine specific aims as follows. (1) To continue the study of Indo-Pacific sponges and extracts in our repository for novel biologically active small molecules (MW 400 - 2000) as a source of new anticancer lead compounds. (2) To collect unexplored sponges as a source of additional small molecules. (3) To create a fungal library for saltwater culture from sponges and their surrounding water column. (4) To create a fungal library for saltwater culture from deepwater sediments. (5) To utilize the NIBRI epigenetic and molecular target-based assays to continue the study of current and future active extracts. (6) To shorten the time from discovery of an active extract to defining its active constituents by creating peak libraries for high throughput screening (HTS) guided isolation, followed by state-of-the-art dereplication or structure elucidation. (7) To use Mass Spec approaches for database mining and metabolomic study, in order to expand the chemodiversity of structural lead compounds. (8) To engage in lead optimization. (9) To obtain patent coverage for important new active compounds.