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）：拟议的研究项目的总体目标是发现生物活性海洋天然产物，从而导致新型化学治疗剂治疗胰腺癌。尽管发生了第十一次发生，但胰腺癌是美国癌症死亡的第四个原因，预计2009年的34,000多人死亡。积极的新组合化学治疗方案与手术相结合，导致平均存活率的总体增长量总体上升，但即使在被诊断为pancreatic癌症诊断的患者中，少于5％的患者也少于5％。显然，需要新的治疗疗法来治疗胰腺癌。 在项目的第一个性能期间，我们朝着开发新的胰腺癌治疗方法方面取得了进步，其中包括：发现左甲甲苯二酚是一种有效的抗象征剂，这是对肿瘤细胞的选择性活性，这些肿瘤细胞会影响微管动力学，但并非直接结合微管蛋白； Neopeltolide是一种通过抑制细胞色素BC1复合物抑制线粒体ATP合成的聚酮化合物。以及甘氮胺A可以恢复胰腺癌细胞中锚定依赖的生长，阻断肿瘤细胞迁移并重新敏感的ASPC-1胰腺癌腺癌癌细胞系以TRAIL诱导的细胞凋亡的发现。在此续签应用中，我们试图继续使用一种前瞻性化学遗传学方法来建立这些成功。拟议的研究的具体目的是：1。从HBOI海洋标本冷冻存储库中的材料分析其能力为1.1的能力。修改已被鉴定为胰腺癌异常激活的关键蛋白质水平，并导致癌细胞存活，对凋亡的抗性以及对当前可用的化学治疗剂的抗性；并阻止胰腺癌细胞系2的扩散，以利用最先进的MS和NMR技术，以快速，准确地消除候选化合物的快速，准确的消除和结构阐明。 3。阐明项目过程中发现的材料的作用方式，并将这些化合物赋予最佳的生物学特征，以将最佳的生物学特征转发为胰腺癌的实验模型。 HBOI保留了20,000多个冷冻海洋标本的存储库，该存储库代表了用于药物发现的独特天然产品集合。我们将使用细胞印记测定法确定针对胰腺癌中异常激活的途径的小分子，并导致患者的存活率较差。我们的最初目标是：丝氨酸/苏氨酸糖原合酶激酶-32（GSK-32），已显示在胰腺癌细胞中激活核因子-KB（NF-KB）转录，从而导致细胞存活和增殖。以及由组成式激活的MAP激酶成员P-MEK和P-ERK导致细胞存活，侵袭和对凋亡的抗性。我们还将继续针对胰腺癌细胞系的小组筛选材料。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，并导致新的，急需的化学治疗剂来治疗胰腺癌。在该项目下发现的化合物可以用作药物本身，被修改以提供改善的药理特性，或用作进一步了解胰腺癌的生化工具。