Discovery of Novel Antitumor Agents Effective Against Pancreatic Cancer

描述（由申请人提供）：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物，从而产生用于治疗胰腺癌的新型化疗药物。虽然胰腺癌的发病率在美国排名第十一，但它是美国癌症死亡的第四大原因，预计2009年将有超过34，000人死亡。积极的新的联合化疗方案加上手术导致平均生存率的总体增加，但即使如此，只有不到5%的胰腺癌患者在诊断后五年内存活。显然，需要新的治疗方法来治疗胰腺癌。 在该项目的第一个执行期间，我们在开发胰腺癌新疗法方面取得了进展，包括以下发现：发现leiodermatitis，一种有效的抗有丝分裂剂，对肿瘤细胞具有选择性活性，影响微管动力学，但不直接结合微管蛋白; neopeltolide，一种聚酮化合物，通过抑制细胞色素bc 1复合物抑制线粒体ATP合成;以及发现曼扎明A可以恢复胰腺癌细胞中的锚定依赖性生长，阻断肿瘤细胞迁移，并使ASPC-1胰腺癌细胞系对TRAIL诱导的细胞凋亡重新敏感。在这次更新申请中，我们寻求继续使用正向化学遗传学方法来建立这些成功。本研究的具体目的是：1.分析来自HBOI海洋标本冷冻库的材料的能力，1.1。改变关键蛋白质的水平，所述关键蛋白质已被鉴定为在胰腺癌中异常激活，并且导致癌细胞存活、对凋亡的抗性和对目前可用的化疗剂的抗性;以及阻断一组胰腺癌细胞系的增殖。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。3.阐明在项目期间发现的材料的作用模式，并将这些化合物用于胰腺癌的实验模型中，这些化合物具有最佳的生物学特性。HBOI拥有超过20，000个冷冻海洋标本的储存库，这些标本代表了用于药物发现的天然产物的独特收藏。我们将使用cyberlot检测来鉴定靶向胰腺癌中异常激活的通路的小分子，这些通路导致患者的生存率低下。我们的初步目标将是：丝氨酸/苏氨酸糖原合成酶激酶-32（GSK-32），其已显示在胰腺癌细胞中激活核因子-kB（NF-kB）转录，导致细胞存活和增殖;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。我们还将继续针对一组胰腺癌细胞系筛选材料。动物模型将在MD安德森（奥兰多）进行。 公共卫生相关性：该项目将继续我们过去的成功，并导致新的，迫切需要的化疗药物治疗胰腺癌。在该项目下发现的化合物本身可用作药物，经修饰以提供具有改善的药理学特性的药物，或用作进一步了解胰腺癌的生化工具。

DESCRIPTION (provided by applicant): 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 34,000 deaths predicted for 2009. 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 leiodermatolide, a potent antimitotic agent with selective activity for tumor cells that effects microtubule dynamics but not though direct binding to tubulin; neopeltolide, a polyketide that inhibits mitochondrial ATP synthesis through inhibition of the cytochrome bc1 complex; 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-32 (GSK-32) which has been shown to activate nuclear factor-kB (NF-kB) 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. Animal models will be conducted at MD Anderson, Orlando. PUBLIC HEALTH RELEVANCE: This project will continue our past successes and lead to new, urgently needed chemotherapeutics for the treatment of pancreatic cancer. The compounds discovered under this project may be used as drugs themselves, modified to provide drugs with improved pharmacological properties or be used as biochemical tools to further understand pancreatic cancer.