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: 7914808
• 负责人: AMY Elizabeth WRIGHT
• 金额: $ 14.94万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914808
• 关键词: Adenocarcinoma Cell; Animal Cancer Model; Antimitotic Agents; Apoptosis; Apoptotic; Arts; Biochemical; Biological; Biological Assay; Cancer Etiology; Cancer cell line; Caribbean region; Cell Cycle Arrest; Cell Line; Cell Survival; Cessation of life; Collection; Complement Factor B; Coupled; Crude Extracts; Development; Diagnosis; Ductal Carcinoma; Experimental Models; Freezing; Genetic Transcription; Glycogen Synthase Kinases; Growth; In Vitro; Lead; Libraries; Library Materials; Link; MEKs; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Marines; 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; 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; Work; abstracting; antitumor agent; calyculin A; cancer cell; cell determination; cell growth; chemical genetics; chemotherapeutic agent; combinatorial chemistry; cytotoxic; cytotoxicity; dictyostatin; drug discovery; in vivo; manzamine A; marine natural product; member; neoplastic cell; novel; novel therapeutics; rapid technique; repository; sample collection; scaffold; small molecule; success; tool; tumor

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.

项目摘要/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 为胰腺癌的治疗提供新的化疗药物。尽管事件发生在第11位， 胰腺癌是美国癌症死亡的第四位原因，预计2007年将有超过3.3万人死亡。 积极的新联合化疗方案与手术相结合，导致了总体上 平均存活率提高，但即便如此，只有不到5%的被诊断为胰腺癌的患者会 确诊后存活五年。显然，治疗胰腺癌需要新的疗法。 在该项目的第一个执行期内，我们取得了进展 治疗胰腺癌的新疗法，包括发现莱迪奥马特利，一种有效的 抗有丝分裂药，对肿瘤细胞具有选择性活性，不通过微管蛋白起作用；新贝列奈，一种 诱导癌细胞G1期停滞的聚酮；以及甘露糖胺A可以恢复 胰腺癌细胞的锚定依赖性生长，阻断肿瘤细胞的迁移，并重新敏化ASPC- 1胰腺癌细胞系以TRAIL诱导细胞凋亡。在此续签申请中，我们寻求 继续使用先进的化学遗传学方法在这些成功的基础上继续发展。 拟议研究的具体目标是： 1.检测来自HBOI海洋标本冷冻库的材料的能力 1.1.改变胰腺癌中被识别为异常激活的关键蛋白的水平 并导致癌细胞存活，抵抗细胞凋亡和抵抗目前可用的 化疗药物；并阻止一组胰腺癌细胞系的增殖 2.利用最先进的MS和核磁共振技术快速准确地进行去复制和结构 候选化合物的说明。 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 这为胰腺癌的实验模型提供了最佳的生物学特征。 HBOI维护着一个超过20,000个冷冻海洋标本的储存库，这些标本代表着 用于药物发现的天然产品。我们将使用细胞印迹分析来鉴定靶向小分子 在胰腺癌中被异常激活并导致患者存活率低的通路。 我们最初的目标是：已经显示的丝氨酸/苏氨酸糖原合成酶-3(GSK-3) 在胰腺癌细胞中激活核因子-β(NF-β)转录，从而导致细胞存活和 增殖；以及结构性激活的MAP激酶成员P-MEK和P-ERK导致 细胞存活、侵袭和抗凋亡。我们还将继续根据一组 胰腺癌细胞株。