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，表征和验证小分子自然产品衍生的低氧诱导因子-1（HIF-1）抑制剂，作为癌症治疗的辅助药物。长期目标是开发特异性靶向肿瘤缺氧（低氧张力）的癌症化学治疗剂。实体瘤含有缺氧区域，缺氧的程度与恶性进展，对放射治疗和化学疗法的抗性以及疾病复发有关。低氧相关的治疗耐药性可以直接由细胞氧浓度降低或间接由缺氧诱导的基因表达修饰引起。我们提出了一种新方法，该方法专门针对缺氧的这种重要间接作用（肿瘤基因表达的改变）。在临床用途中没有批准的药物专门针对缺氧。该药物发现​​计划独特地将天然产品化学与尖端生物医学研究结合在一起。具体目标1将评估富含天然产物的提取物，分离和阐明活性铅的化学结构，这些铅的化学结构抑制缺氧诱导的和/或组成型激活的HIF-1，这是激活缺氧下适应和存活基因表达的主要转录因子。 HIF-1不仅促进了缺氧性肿瘤的存活和转移，HIF-1的致癌激活还与恶性进展和耐药性有关。将在一组HIF-1抑制活性（低氧诱导的和致癌）的高通量生物测定面板中检查富含天然产物的提取物。活性化合物将通过生物测定指导的隔离分离，并使用光谱和光谱法的组合阐明其结构。通过发现一些最有效的小分子HIF-1抑制剂，已经确定了原理证明。具体目标2将确定活性化合物对低氧肿瘤细胞存活，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系列肿瘤细胞系将用作体外模型。在基因设计的鼠类乳腺癌模型中，将进一步研究抑制低氧肿瘤细胞存活，血管生成和转移的无毒活性化合物。特定的目标3将研究自然产物衍生的HIF抑制剂作为化学治疗剂的辅助药物的治疗潜力。目的是确定HIF-1抑制剂与化学疗法的最佳组合，这些抑制剂可以达到抑制低毒性的抑制肿瘤生长的最大疗效。特定的目标4将在分子和细胞水平上表征天然产物衍生的HIF抑制剂，并解决作用机理。实现这些目标将提供抗肿瘤药物铅和分子探针，这些探针将为介导低氧信号传导的细胞内途径提供新的见解。公共卫生相关性：该项目与公共卫生高度相关，因为目标是发现和开发新药来治疗乳腺癌，前列腺和其他形式的癌症。拟议的研究旨在发现肿瘤选择性的小分子，这些分子的副作用明显少于大多数当前的化学治疗剂。这些化合物将靶向肿瘤环境中独特的生理差异，以及肿瘤细胞中特定的遗传差异，即使在被剥夺氧气的条件下，它们也可以生存和生长。