Discovery of Novel Antitumor Agents Effective Against Pancreatic Cancer

项目概要/摘要 拟议研究项目的总体目标是发现具有生物活性的海洋天然产品， 导致用于治疗胰腺癌的新的化学治疗剂。虽然第十一次出现， 胰腺癌是美国癌症死亡的第四大原因，2007年预计有超过33，000人死亡。 积极的新的联合化疗方案加上手术导致了整体 平均生存率增加，但即使如此，只有不到5%的胰腺癌患者会 诊断后存活五年。显然，需要新的治疗方法来治疗胰腺癌。 在项目的第一个执行期，我们在开发 新的治疗胰腺癌的方法，包括发现，如：leideormatrixate的发现，一种有效的 抗有丝分裂剂，对肿瘤细胞具有选择性活性，不通过微管蛋白起作用;新倍妥内酯，一种 在癌细胞中诱导G1细胞周期停滞的聚酮化合物;以及发现曼扎明A可以恢复 胰腺癌细胞的锚定依赖性生长，阻断肿瘤细胞迁移并使ASPC重新敏感， 1胰腺癌细胞系对TRAIL诱导的凋亡作用。在这份更新申请中，我们寻求 继续使用先进的化学遗传学方法，以这些成功为基础。 拟议研究的具体目标是： 1.分析来自HBOI海洋标本冷冻库的材料， 1.1.改变在胰腺癌中被确定为异常激活的关键蛋白质的水平 并导致癌细胞存活、对凋亡的抵抗和对目前可用的抗肿瘤药物的抵抗。 化疗剂;并阻断一组胰腺癌细胞系的增殖 2.利用最先进的MS和NMR技术进行快速准确的去复制和结构分析 候选化合物的说明。 3.阐明项目期间发现的材料的作用模式，并将这些化合物 这为胰腺癌的实验模型提供了最佳的生物学特征。 HBOI保存了超过20，000个冷冻海洋标本，代表了一个独特的收藏， 天然产物用于药物发现。我们将使用Cyberlot检测来鉴定靶向 这些通路在胰腺癌中异常激活，导致患者存活率低。 我们最初的目标是：丝氨酸/苏氨酸糖原合成酶激酶-3（GSK-3）， 激活核因子-？B（NF-？B）胰腺癌细胞中的转录导致细胞存活， 以及MAP激酶成员P-MEK和P-ERK，其被组成性激活，导致 细胞存活、侵袭和抗凋亡。我们还将继续对材料进行筛选， 胰腺癌细胞系。

Project Summary/Abstract The overall objective of the proposed research project is to discover bioactive marine natural products that lead to novel chemotherapeutics for the treatment of pancreatic cancer. Although eleventh in occurrence, pancreatic cancer is the fourth cause of cancer death in the US, with over 33,000 deaths predicted for 2007. Aggressive new combination chemotherapeutic regimes coupled with surgery have resulted in an overall increase in mean survival rate, but even so, fewer than 5% of patients diagnosed with pancreatic cancer will survive five years post diagnosis. Clearly, novel therapeutics are required to treat pancreatic cancer. During the first performance period of the project we made advancements towards the development of new treatments for pancreatic cancer, including findings such as: the discovery of leideormatolide, a potent antimitotic agent, with selective activity for tumor cells, that does not work via tubulin; neopeltolide, a polyketide that induces G1 cell cycle arrest in cancer cells; and the finding that manzamine A can restore anchorage dependent growth in pancreatic cancer cells, block tumor cell migration and re-sensitize the ASPC- 1 pancreatic adenocarcinoma cancer cell line to TRAIL induced apoptosis. In this renewal application we seek to continue to use a forward chemical genetics approach to build upon these successes. The Specific Aims of the proposed research are: 1. To assay materials from the HBOI marine specimen frozen repository for their ability to 1.1. modify levels of key proteins that have been identified as aberrantly activated in pancreatic cancers and which lead to cancer cell survival, resistance to apoptosis and resistance to currently available chemotherapeutic agents; and block the proliferation of a panel of pancreatic cancer cell lines 2. To utilize state-of-the-art MS and NMR techniques for rapid and accurate dereplication and structure elucidation of candidate compounds. 3. To elucidate the mode of action of materials discovered during the project and to take those compounds which give the best biological profiles forward into experimental models of pancreatic cancer. HBOI maintains a repository of over 20,000 frozen marine specimens which represent a unique collection of natural products for drug discovery. We will use the cytoblot assay to identify small molecules that target pathways that are aberrantly activated in pancreatic cancers and which lead to poor survival rates in patients. Our initial targets will be: the serine/threonine glycogen synthase kinase-3¿ (GSK-3¿) which has been shown to activate nuclear factor-?B (NF-?B) transcription in pancreatic cancer cells leading to cell survival and proliferation; and the MAP kinase members P-MEK and P-ERK which are constitutively activated leading to cell survival, invasion and resistance to apoptosis. We will also continue to screen materials against a panel of pancreatic cancer cell lines.