Discovery of Novel Antitumor Agents Effective Against Pancreatic Cancer

发现有效对抗胰腺癌的新型抗肿瘤药物

• 批准号: 8090437
• 负责人: AMY Elizabeth WRIGHT
• 金额: $ 31.66万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090437
• 关键词: ATP Synthesis Pathway; Adenocarcinoma Cell; Affect; Animal Cancer Model; Animal Model; Antimitotic Agents; Apoptosis; Apoptotic; Binding; Biochemical; Biological; Biological Assay; Cancer Etiology; Cancer cell line; Caribbean region; Cell Line; Cell Proliferation; Cell Survival; Cessation of life; Collection; Coupled; Crude Extracts; Cytochrome bc1 Complex; Development; Diagnosis; Ductal Carcinoma; Experimental Models; Freezing; Genetic Transcription; Glycogen Synthase Kinases; Growth; In Vitro; Lead; Libraries; Library Materials; Link; MAP2K1 gene; MAPK1 gene; MAPK3 gene; MEKs; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Marines; Microtubules; Mitochondria; Mitogen-Activated Protein Kinases; Mutation; Natural Product Drug; Neoplasm Metastasis; Nuclear; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Performance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Property; Proteins; Proto-Oncogenes; Research; Research Project Grants; Resistance; Sea; Serine; Signal Transduction Pathway; Specimen; Stimulus; Structure; Structure-Activity Relationship; Survival Rate; TNFSF10 gene; Text; Threonine; Topoisomerase II inhibition; Tubulin; antitumor agent; calyculin A; cancer cell; chemical genetics; chemotherapeutic agent; combinatorial chemistry; dictyostatin; drug discovery; improved; in vivo; insight; manzamine A; marine natural product; member; neoplastic cell; novel; novel therapeutics; pancreatic cancer cells; public health relevance; rapid technique; repository; sample collection; scaffold; small molecule; success; therapeutic target; tool; tumor

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.

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十一位，但它是美国第四大癌症死亡原因，预计 2009 年将有超过 34,000 人死亡。积极的新联合化疗方案与手术相结合，导致平均生存率总体提高，但即便如此，死亡人数也有所减少。超过 5% 的胰腺癌患者在诊断后能够存活五年。显然，需要新的疗法来治疗胰腺癌。 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：发现了leiodermatolide，一种有效的抗有丝分裂剂，对肿瘤细胞具有选择性活性，可影响微管动力学，但不直接结合至微管蛋白； neopeltolide，一种聚酮化合物，通过抑制细胞色素 bc1 复合物来抑制线粒体 ATP 合成；研究发现，manzamine A 可以恢复胰腺癌细胞的贴壁依赖性生长，阻止肿瘤细胞迁移，并使 ASPC-1 胰腺腺癌细胞系对 TRAIL 诱导的细胞凋亡重新敏感。在此更新应用中，我们寻求继续使用正向化学遗传学方法来巩固这些成功。拟议研究的具体目标是： 1. 分析 HBOI 海洋标本冷冻库中的材料的 1.1 能力。修改已被确定在胰腺癌中异常激活的关键蛋白质的水平，这些蛋白质会导致癌细胞存活、对细胞凋亡的抵抗以及对当前可用化疗药物的抵抗；并阻断一组胰腺癌细胞系的增殖 2. 利用最先进的 MS 和 NMR 技术快速准确地对候选化合物进行去复制和结构阐明。 3. 阐明项目期间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应用于胰腺癌的实验模型中。 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独特天然产物集合。我们将使用细胞印迹分析来识别小分子，这些小分子针对胰腺癌中异常激活的通路，这些通路会导致患者的生存率较低。我们最初的目标是：丝氨酸/苏氨酸糖原合成酶激酶 32 (GSK-32)，它已被证明可以激活胰腺癌细胞中的核因子 -kB (NF-kB) 转录，从而导致细胞存活和增殖； MAP 激酶成员 P-MEK 和 P-ERK 被组成型激活，导致细胞存活、侵袭和抵抗细胞凋亡。我们还将继续针对一组胰腺癌细胞系筛选材料。动物模型将在奥兰多 MD 安德森进行。 公共健康相关性：该项目将延续我们过去的成功，并带来新的、迫切需要的胰腺癌化疗药物。该项目发现的化合物本身可以用作药物，经过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。