Discovery of Anticancer Drugs from Cyanophytes

从蓝藻中发现抗癌药物

基本信息

批准号：
8117215
负责人：
FREDERICK Augustus VALERIOTE
金额：
$ 38.4万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117215
关键词：
Algae Animal Model Antineoplastic Agents Applications Grants Aquaculture Biological Assay Biological Factors Biology Biomass Breast California Cancer Center Cancer Patient Characteristics Chemical Structure Chemicals Chemistry Clinic Clinical Collaborations Collection Coupled Crude Extracts Cyanobacterium Data Detection Development Diffusion Disease Dose Drug Administration Schedule Drug Kinetics Epigenetic Process Evaluation Foundations Fractionation Gene Cluster Genes Goals Grant Health Health system High Pressure Liquid Chromatography In Vitro Inhibitory Concentration 50 Institution Laboratories Lead Malignant neoplasm of brain Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Marines Materials Testing Maximum Tolerated Dose Methods Modification Molecular Monitor Mus Oceanography Organism Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phylogenetic Analysis Plasma Regulatory Pathway Relative (related person)Research Route Sampling Scheme Screening procedure Serum Solid Solid Neoplasm Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staging Structure Structure-Activity Relationship System Testing Therapeutic Tissues Toxic effect Treatment Efficacy Universities Water Xenograft Model analog anticancer activity base cancer cell cytotoxicity drug development drug discovery efficacy trial in vitro Assay in vivo innovation interest intravenous administration marine natural product microbial novel pre-clinical programs rectal therapeutic effectiveness tissue culture tumor

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is the discovery and development of new anticancer drugs with solid tumor selectivity from leads obtained from collected and cultured marine cyanobacteria and marine microalgae. The need for new and effective anticancer drugs is critical given the paucity of ones active against the major solid tumors in people. Over the course of this grant, 450 taxonomically diverse samples are proposed to be obtained as a source of novel natural products. Micro-elicitation culture methods will be employed on a set of these samples to thoroughly query their secondary metabolomes. Nine fractions plus crude extract are produced from each organism for the anticancer screen (over 900 test samples per year). We employ a unique and novel disk diffusion assay to both identify solid tumor selectivity in the initial extracts and also to direct the isolation of the putative anticancer agent. The assay has been expanded to examine the 7 major solid tumor types in vitro and then in vivo. We expect to both functionally and structurally identify about 6 solid tumor selective compounds per year. While many of the leads will be novel structures, some of the leads may be known compounds or analogues of known compounds; however, very few of these latter compounds will have been evaluated for anticancer activity either in vitro or in vivo. We expect to take all of our lead compounds through a drug development paradigm so as to determine whether they have clinical potential. The first step of drug development requires 15 mg of pure compound to produce in vitro IC50 values and concentration-survival clonogenic studies; and, in vivo maximum tolerated dose and pharmacokinetic information (plasma and tumor levels). The drug is formulated for intravenous administration and an HPLC assay is developed to monitor serum and tissue levels. We expect that all 6 of the yearly discovered in vitro lead compounds will be examined in this pharmacologic phase. These data will be analyzed to determine whether the more expensive efficacy trials in tumor-bearing mice should be undertaken. We expect 3 drugs per year will go to therapeutic efficacy trial in at least one xenograft model. Such a trial will likely require a further collection, culturing or synthetic efforts to gain sufficient material, estimated at 50 - 200 mg. We expect to find one compound per year that has efficacy in the xenograft models, and this lead structure will be chemically explored through synthesis of simple analogs and synthetic modification of the natural product. Therapeutically active drugs will be pursued further in preclinical and clinical development outside of this application. PUBLIC HEALTH RELEVANCE: Anticancer drug leads will be discovered, their structure determined and developed both in tissue culture and animal models to a stage where they should be attractive to either Biotech or Pharmaceutical companies to continue with their development towards the clinic. Given the lack of effective anticancer drugs for the major solid tumors, especially for metastatic disease, our leads can have a significant positive impact on the cancer patient.

描述（由申请人提供）：该项目的总体目标是从收集和培养的海洋蓝细菌和海洋微藻中获得的先导化合物中发现和开发具有实体瘤选择性的新抗癌药物。鉴于缺乏有效对抗人类主要实体瘤的药物，对新的有效抗癌药物的需求至关重要。在这笔拨款的过程中，拟获取 450 个分类学上不同的样本作为新型天然产品的来源。将在一组这些样品上采用微诱导培养方法，以彻底查询其次级代谢组。从每种生物体中产生九种级分和粗提物用于抗癌筛选（每年超过 900 个测试样品）。我们采用独特且新颖的纸片扩散测定来识别初始提取物中的实体瘤选择性，并指导假定的抗癌剂的分离。该检测已扩展到体外和体内检查 7 种主要实体瘤类型。我们期望每年从功能和结构上鉴定出约 6 种实体瘤选择性化合物。虽然许多先导化合物是新颖的结构，但一些先导化合物可能是已知化合物或已知化合物的类似物；然而，后面这些化合物中很少有在体外或体内进行过抗癌活性评估。我们希望通过药物开发范例来采用我们所有的先导化合物，以确定它们是否具有临床潜力。药物开发的第一步需要15毫克纯化合物来产生体外IC50值和浓度-生存克隆形成研究；以及体内最大耐受剂量和药代动力学信息（血浆和肿瘤水平）。该药物专为静脉注射而配制，并开发了 HPLC 测定法来监测血清和组织水平。我们预计每年发现的所有 6 种体外先导化合物都将在此药理学阶段进行检查。将分析这些数据以确定是否应该在荷瘤小鼠中进行更昂贵的疗效试验。我们预计每年有 3 种药物将在至少一种异种移植模型中进行疗效试验。这样的试验可能需要进一步收集、培养或合成努力以获得足够的材料，估计为 50 - 200 毫克。我们期望每年找到一种在异种移植模型中有效的化合物，并且将通过简单类似物的合成和天然产物的合成修饰来化学探索这种先导结构。除本申请外，还将在临床前和临床开发中进一步寻求治疗活性药物。公共健康相关性：抗癌药物先导物将被发现，其结构将在组织培养和动物模型中确定和开发，达到对生物技术或制药公司有吸引力的阶段，以继续其临床开发。鉴于主要实体瘤缺乏有效的抗癌药物，尤其是转移性疾病，我们的研究成果可以对癌症患者产生显着的积极影响。