New Anticancer Agents from Atlantic and Caribbean

癌症仍然是美国第二大死亡原因。据估计，在2004年期间，美国将有超过560，000人死于癌症，并且将诊断出1，368，030个新病例。从历史上看，天然产物或以它们为模型的化合物在癌症治疗中具有重要的实用性。许多海洋衍生化合物目前正在临床研究中用于治疗癌症，包括discodermolide，一种在HBOI从深水海绵中发现的化合物，并由诺华公司带到诊所。我们对肿瘤进展的理解的进展为癌症的干预提供了新的靶点，并且选择性作用于这些靶点的化合物的发现已经开始提供具有有限（如果有的话）副作用的新疗法。在本建议中，我们将继续 证实了我们的假设，即可以发现在这些确定的分子靶标上相互作用的海洋天然产物（MNP），并且这些化合物或以它们为模型的化合物将用于治疗癌症。该项目将与诺华生物医学研究所合作开展。（NIBRI）、加州大学圣克鲁斯分校（UCSC）的Crews MNP小组、俄勒冈州州立大学（OSU）的Gerwick小组和斯克里普斯海洋学研究所（SIO）的Fenical小组。HBOI为NCDDG带来了一套互补的生物体和专业知识。本项目的具体目标如下： 1.建立一个来自大西洋和加勒比海海洋生物的高度富集级分/纯物质的多样性和互补性文库（“峰值文库”）。2.将材料提交给NIBRI进行表观遗传学和分子筛选小组的检测，并在必要时使用这些检测进行纯化。3.利用最先进的质谱和核磁共振技术对候选化合物进行快速准确的去重复和结构解析。4.向NIBRI提供足够的化合物，以便进行二次生物学试验和随访。

Cancer remains the second leading cause of death in the United States. It is estimated that over 560,000 individuals in the US will die from cancer during 2004 and 1,368,030 new cases will be diagnosed. Historically, natural products or compounds modeled on them, have found significant utility in the treatment of cancer. A number of marine-derived compounds are currently under clinical investigation for the treatment of cancer, including discodermolide, a compound discovered at HBOI from a deep-water sponge, and brought to the clinic by Novartis. Advances in our understanding of neoplastic progression have provided new targets for intervention in cancer and the discovery of compounds which selectively act on these targets has begun to provide novel therapies with limited, if any, side effects. In this proposal we will continue to substantiate our hypothesis that marine natural products (MNPs) can be discovered which interact at these defined molecular targets and that these compounds, or compounds modeled upon them, will be useful in the treatment of cancer. The project will be carried out in collaboration with the Novartis Institute of Biomedical Research, Inc. (NIBRI), the Crews MNP group at UC Santa Cruz (UCSC), the Gerwick group at Oregon State University (OSU) and the Fenical group at Scripps Institute of Oceanography (SIO). HBOI brings to the NCDDG a complementary set of organisms and expertise. The Specific Aims for this Project are as follows: 1. To create a diverse and complementary library of highly enriched fractions/pure materials ("a peak library") derived from Atlantic and Caribbean marine organisms. 2. To submit the materials to NIBRI for assay in their panel of epigenetic and molecular screens and use these assays to follow purification when necessary. 3. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 4. To provide sufficient compound to the NIBRI to allow for secondary biological testing and follow up.