ANTICANCER DRUG DISCOVERY THAT TARGETS TUMOR HYPOXIA

针对肿瘤缺氧的抗癌药物的发现

基本信息

批准号：
8071564
负责人：
DALE G NAGLE
金额：
$ 26.21万
依托单位：
UNIVERSITY OF MISSISSIPPI
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：
2004-05-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071564
关键词：
Adverse effects Antineoplastic Agents Biological Assay Biological Factors Biomedical Research Breast Breast Cancer Model Cancer Patient Cell Survival Chemical Structure Chemicals Clinical Clinical Trials Development Disease Engineering Environment Gene Expression Genes Genetic Goals Health Homeostasis Hypoxia In Vitro Lead Malignant - descriptor Malignant Neoplasms Mediating Methods Modification Molecular Molecular Probes Molecular Target Mus Natural Products Chemistry Neoplasm Metastasis Oncogenic Oxygen Oxygen measurement, partial pressure, arterial Pathway interactions Pharmaceutical Preparations Physiological Play Prostate Public Health Radiation Recurrent disease Research Resistance Role Signal Transduction Solid Neoplasm Source Staging Structure Therapeutic Toxic effect Treatment outcome Tumor Angiogenesis Tumor Cell Line activating transcription factor advanced disease angiogenesis antitumor drug cancer prevention cancer therapy chemotherapeutic agent chemotherapy drug discovery hypoxia inducible factor 1 improved in vitro Model inhibitor/antagonist insight neoplastic cell novel novel strategies preclinical study programs response small molecule statistics transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The objective of the proposed research is to discover, characterize, and validate small molecule natural product-derived hypoxia-inducible factor-1 (HIF-1) inhibitors as adjunct agents for cancer therapy. The long-term goal is to develop cancer chemotherapeutic agents that specifically target tumor hypoxia (low oxygen tension). Solid tumors contain hypoxic regions and the extent of hypoxia correlates with malignant progression, resistance to radiation treatment and chemotherapy, and relapse of the disease. Hypoxia-associated treatment resistance can be caused directly by reduced cellular oxygen concentrations or indirectly by hypoxia-induced modifications in gene expression. We propose a new approach that specifically targets this important indirect effect of hypoxia (alteration of tumor gene expression). There is no approved drug in clinical use that specifically targets hypoxia. This drug discovery program uniquely combines natural products chemistry with cutting edge biomedical research. Specific Aim 1 will evaluate natural product-rich extracts, isolate and elucidate the chemical structures of active leads that inhibit hypoxia-induced and/or constitutively activated HIF-1, the principle transcription factor that activates the expression of adaptation and survival genes under hypoxia. Not only does HIF-1 promote hypoxic tumor survival and metastasis, oncogenic activation of HIF-1 is also associated with malignant progression and treatment resistance. Natural product-rich extracts will be examined in a panel of high-throughput bioassays for HIF-1 inhibitory activities (hypoxia-induced and oncogenically activated). Active compounds will be isolated through bioassay-guided isolation, and their structures elucidated using a combination of spectroscopic and spectrometric methods. Proof of principle has been established by the discovery of some of the most potent small molecule HIF-1 inhibitors. Specific Aim 2 will determine the effects of active compounds on hypoxic tumor cell survival, angiogenesis, and metastasis. A panel of tumor cell lines that represent different disease stages and hypoxia responsiveness will be used as in vitro models. Nontoxic active compounds that inhibit hypoxic tumor cell survival, angiogenesis, and metastasis in vitro will be further investigated in genetically engineered murine breast cancer models. Specific Aim 3 will investigate the therapeutic potential of natural product-derived HIF inhibitors as adjunct agents with chemotherapeutic agents. The goal is to identify the optimal combination of HIF-1 inhibitors with chemotherapy that can achieve the maximum efficacy of inhibiting tumor growth with low toxicity. Specific Aim 4 will characterize natural product-derived HIF inhibitors at the molecular and cellular levels and resolve the mechanisms of action. Accomplishing these objectives will provide antitumor drug leads and molecular probes that will afford new insights into the intracellular pathways that mediate hypoxic signaling. PUBLIC HEALTH RELEVANCE: This project is highly relevant to public health because the goals are to discover and develop new drugs to treat breast, prostate, and other forms of cancer. The proposed research is aimed at the discovery of tumor-selective small molecules that will have markedly fewer side effects and less toxicity than most current chemotherapeutic agents. These compounds will target unique physiological differences in the tumor environment and specific genetic differences in tumor cells that allow them to survive and grow even under conditions where they are deprived of oxygen.

描述（由申请人提供）：拟议研究的目的是发现、表征和验证小分子天然产物衍生的缺氧诱导因子 1 (HIF-1) 抑制剂作为癌症治疗的辅助药物。长期目标是开发专门针对肿瘤缺氧（低氧张力）的癌症化疗药物。实体瘤含有缺氧区域，缺氧程度与恶性进展、对放射治疗和化疗的抵抗以及疾病的复发相关。缺氧相关的治疗抵抗可能是由细胞氧浓度降低直接引起的，也可能是由缺氧诱导的基因表达改变间接引起的。我们提出了一种新方法，专门针对缺氧的这种重要的间接影响（肿瘤基因表达的改变）。临床上尚无专门针对缺氧的批准药物。该药物发现计划将天然产物化学与尖端生物医学研究独特地结合起来。具体目标 1 将评估富含天然产物的提取物，分离并阐明抑制缺氧诱导和/或组成型激活的 HIF-1 的活性先导化合物的化学结构，HIF-1 是在缺氧条件下激活适应和生存基因表达的主要转录因子。 HIF-1 不仅促进缺氧肿瘤的存活和转移，HIF-1 的致癌激活还与恶性进展和治疗耐药相关。富含天然产物的提取物将通过一系列高通量生物测定来检测 HIF-1 抑制活性（缺氧诱导和致癌激活）。将通过生物测定引导的分离来分离活性化合物，并使用光谱和光谱测定方法相结合来阐明其结构。一些最有效的小分子 HIF-1 抑制剂的发现已经证实了原理。具体目标 2 将确定活性化合物对缺氧肿瘤细胞存活、血管生成和转移的影响。代表不同疾病阶段和缺氧反应性的一组肿瘤细胞系将被用作体外模型。将在基因工程小鼠乳腺癌模型中进一步研究体外抑制缺氧肿瘤细胞存活、血管生成和转移的无毒活性化合物。具体目标 3 将研究天然产物衍生的 HIF 抑制剂作为化疗药物辅助药物的治疗潜力。目标是确定 HIF-1 抑制剂与化疗的最佳组合，以实现抑制肿瘤生长的最大功效且毒性低。具体目标 4 将在分子和细胞水平上表征天然产物衍生的 HIF 抑制剂，并解析其作用机制。实现这些目标将提供抗肿瘤药物先导物和分子探针，从而为介导缺氧信号传导的细胞内途径提供新的见解。公共健康相关性：该项目与公共健康高度相关，因为其目标是发现和开发治疗乳腺癌、前列腺癌和其他形式癌症的新药。拟议的研究旨在发现肿瘤选择性小分子，与大多数现有化疗药物相比，其副作用和毒性显着减少。这些化合物将针对肿瘤环境中独特的生理差异和肿瘤细胞的特定遗传差异，使它们即使在缺氧的条件下也能生存和生长。