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，从而开发出治疗胰腺癌的新型化疗药物。虽然胰腺癌的发病率排在第11位，但它是美国癌症死亡的第四位原因，预计2009年将有超过3.4万人死亡。积极的新联合化疗方案与手术相结合，总体上提高了平均存活率，但即便如此，被诊断为胰腺癌的患者中，只有不到5%的人能在确诊后存活五年。显然，治疗胰腺癌需要新的疗法。在该项目的第一个实施期，我们在开发胰腺癌新疗法方面取得了进展，包括发现：发现Leiodermatolide是一种有效的抗有丝分裂药物，对肿瘤细胞具有选择性，可影响微管动力学，但不直接与微管蛋白结合；neopeltolide，一种多酮，通过抑制细胞色素Bc1复合体抑制线粒体ATP的合成；以及发现甘露糖胺A可以恢复胰腺癌细胞的锚定依赖生长，阻断肿瘤细胞的迁移，并使ASPC-1胰腺癌细胞株对TRAIL诱导的细胞凋亡重新增敏。在这次续签申请中，我们寻求继续使用一种先进的化学遗传学方法来建立在这些成功的基础上。拟议研究的具体目标是：1.检测HBOI海洋标本冷冻库中的材料对1.1的能力。改变在胰腺癌中被鉴定为异常激活的关键蛋白的水平，这些关键蛋白导致癌细胞存活、对凋亡的抵抗和对当前可用的化疗药物的抗药性；并阻止一组胰腺癌细胞的增殖2.利用最先进的MS和核磁共振技术快速准确地去复制和确定候选化合物的结构。3.阐明项目中发现的材料的作用方式，并将那些具有最佳生物学特性的化合物引入胰腺癌的实验模型。HBOI拥有20,000多个冷冻海洋标本的储存库，这些标本代表着用于药物发现的独特的天然产品集合。我们将使用细胞印迹分析来识别靶向胰腺癌中异常激活并导致患者存活率低下的通路的小分子。我们最初的目标将是：丝氨酸/苏氨酸糖原合成酶激酶-32(GSK-32)，它已被证明激活了胰腺癌细胞中的核因子-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，它们被结构性激活，导致细胞存活、侵袭和抵抗凋亡。我们还将继续针对一组胰腺癌细胞株筛选材料。动物模型将在奥兰多的MD Anderson进行。 公共卫生相关性：该项目将继续我们过去的成功，并导致治疗胰腺癌的新的、迫切需要的化疗药物。在该项目下发现的化合物可能被用作药物本身，经过修改以提供具有更好药理特性的药物，或者被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.