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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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导致了治疗胰腺癌的新型化疗药物，尽管出现次数排在第十一位。胰腺癌是美国第四大癌症死亡原因，预计 2007 年将有超过 33,000 人死亡。积极的新联合化疗方案与手术相结合已导致总体平均生存率增加，但即便如此，诊断出胰腺癌的患者中只有不到 5% 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，我们在开发胰腺癌的新疗法，包括以下发现： leideormatolide 的发现，一种有效的抗有丝分裂剂，对肿瘤细胞具有选择性活性，不通过微管蛋白（一种微管蛋白）发挥作用；聚酮化合物可诱导癌细胞 G1 细胞周期停滞，并且发现曼扎明 A 可以恢复细胞周期；胰腺癌细胞贴壁依赖性生长，阻止肿瘤细胞迁移并重新敏化 ASPC- 1 胰腺腺癌细胞系 TRAIL 诱导细胞凋亡在此更新应用中，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能力 1.1. 改变已被确定在胰腺癌中异常激活的关键蛋白质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 NMR 技术进行快速、准确的去重复和结构候选化合物的阐明。 3. 阐明项目期间发现的材料的作用方式并采取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 拥有超过 20,000 个冷冻海洋标本的储存库，这些标本代表了独特的收藏我们将使用细胞印迹分析来识别靶向的小分子。胰腺癌中异常激活的通路导致患者存活率低。我们最初的目标是：丝氨酸/苏氨酸糖原合酶激酶-3¿ (GSK-3¿) 已显示激活胰腺癌细胞中的核因子-κB (NF-κB) 转录，从而导致细胞存活和增殖；以及 MAP 激酶成员 P-MEK 和 P-ERK 被组成型激活，导致我们还将继续针对一组细胞筛选材料。胰腺癌细胞系。