ANTICANCER DRUG DISCOVERY THAT TARGETS TUMOR HYPOXIA

针对肿瘤缺氧的抗癌药物的发现

• 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
• 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

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。实体肿瘤含有缺氧区，缺氧的程度与恶性进展、对放疗和化疗的抵抗以及疾病的复发有关。低氧相关的处理抗性可以由细胞氧浓度降低直接引起，也可以通过低氧诱导的基因表达改变间接引起。我们提出了一种新的方法，专门针对这种重要的间接影响缺氧（肿瘤基因表达的改变）。目前还没有临床批准的药物专门针对缺氧。这个药物发现项目独特地将天然产物化学与尖端生物医学研究相结合。Specific Aim 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/或组成性激活的HIF-1的活性导联的化学结构，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不仅促进肿瘤缺氧生存和转移，其致癌激活也与恶性进展和治疗抵抗有关。天然产物丰富的提取物将在一组高通量生物测定中检测HIF-1抑制活性（缺氧诱导和致癌激活）。活性化合物将通过生物测定引导分离分离，它们的结构将通过光谱学和光谱法的结合来阐明。通过发现一些最有效的小分子HIF-1抑制剂，已经建立了原理证明。特异性目的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。一组代表不同疾病阶段和缺氧反应的肿瘤细胞系将被用作体外模型。抑制体外缺氧肿瘤细胞存活、血管生成和转移的无毒活性化合物将在基因工程小鼠乳腺癌模型中进一步研究。特异性目标3将研究天然产物衍生的HIF抑制剂作为化疗药物辅助剂的治疗潜力。目的是确定HIF-1抑制剂与化疗的最佳组合，以达到低毒性抑制肿瘤生长的最大功效。特异性Aim 4将在分子和细胞水平上表征天然产物衍生的HIF抑制剂，并解决其作用机制。实现这些目标将提供抗肿瘤药物线索和分子探针，这将为介导缺氧信号的细胞内通路提供新的见解。公共卫生相关性：该项目与公共卫生高度相关，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，这些小分子的副作用和毒性明显低于大多数目前的化疗药物。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中特定的遗传差异，这些差异使它们即使在缺氧的条件下也能存活和生长。