Targeting Glioblastoma Using Novel Small Molecule HIF-1 Pathway Inhibitors

使用新型小分子 HIF-1 通路抑制剂靶向胶质母细胞瘤

基本信息

批准号：
7915838
负责人：
ERWIN G VAN MEIR
金额：
$ 4.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915838
关键词：
Adjuvant Radiotherapy Affect Angiogenic Factor Animal Cancer Model Animal Disease Models Animal Model Anoxia Apoptotic Area Astrocytoma Behavior Benzopyrans Biodistribution Biological Assay Biological Factors Biological Models Blood - brain barrier anatomy Cancer Patient Cell Culture Techniques Cell Fraction Cells Characteristics Chemical Structure Clinical Treatment Clinical Trials Comparative Study Data Development Drug Kinetics Effectiveness Electrodes Environment Enzymes Evaluation Experimental Models Gene Targeting Genetic Genetic Transcription Glioblastoma Glioma Goals Growth Health Human Hypoxia Image Immunohistochemistry In Vitro Injection of therapeutic agent Knock-out LacZ Genes Lead Libraries Luciferases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Measurement Mediating Messenger RNA Metabolic Metabolism Modeling Molecular Molecular Target Mus National Cancer Institute Necrosis Neoplasm Metastasis Nuclear Oxygen Pathway interactions Patients Permeability Pharmaceutical Preparations Pharmacodynamics Physiological Pimonidazole Polyribosomes Post-Translational Protein Processing Property Protein Inhibition Proteins Radiation therapy Radio Radiolabeled Rattus Reporter Reporter Genes Research Personnel Resistance Rodent Safety Screening procedure Signal Pathway Signal Transduction Solid Neoplasm Specificity Staining method Stains Structure Structure-Activity Relationship Systems Biology Testing Therapeutic Therapeutic Agents Time Tissues Toxicology Translating Translations Tumor Angiogenesis Vascularization Xenograft procedure angiogenesis base cancer cell cancer therapy cancer type cellular targeting chemotherapeutic agent chemotherapy combinatorial design effective therapy environmental change expectation improved in vitro activity in vivo inhibitor/antagonist innovation luminescence neoplastic cell novel novel strategies overexpression preclinical study pressure programs radiotracer response small molecule transcription factor tumor tumor growth tumor progression

项目摘要

There is an urgent need to develop novel therapies for malignant solid tumors. Tumor hypoxia, a reduction In partial oxygen pressure is a characteristic of solid tumor growth and develops following insufficient oxygen supply from preexisting vasculature. This phenomenon stimulates tumor progression by activating physiological responses that permit tumor-induced angiogenesis and metabolic adaptation to growth under a hypoxic environment. It is also a major factor in the resistance of cancer cells to radio- and chemo-therapies. Hypoxia triggers activation of Hypoxia-lnducible Factor 1 (HIF-1), a transcription factor that drives transcription of genes encoding pro-angiogenic factors and glycolytic enzymes that contribute to tumor growth. Strategies that inhibit HIF-1 function through HIF-1a knockdown or knockout approaches have reduced tumor growth in experimental models including glioblastoma, the most malignant brain tumor for which there is currently no effective therapy. Here we would like to test the hypothesis that small molecules that inhibit the HIF-1 pathway will inhibit the growth of glioblastoma, either singly or in combination with other agents. We have developed a novel pipeline of such potential therapeutic agents by screening a natural product-like library of small molecular compounds using a HIF-1-responsive cell-based reporter assay. We have generated extensive preliminary data showing that two structural classes of compounds identified have potent anti-HIF activity in vitro and in vivo. Furthermore, we have found that our lead HIF inhibitor acts via a unique mechanism and is able to strongly inhibit in vivo tumor growth upon systemic administration.Here we plan to further develop these lead molecules, test them further in animal models of glioblastoma as a model for an aggressivesolid tumor relying on HIF-1 activation for its growth, and determine their precise mechanism of action. These studies are innovative in that these molecules have a novel unique chemical structure and mechanism of action, and there is a pressing need for small molecule HIF pathway inhibitors. These small molecules have great potential as candidate therapeutics for a large number of solid tumors that rely on the HIF pathway for their growth. These preclinical studies have the potential to directly benefit human health by increasing the survival of cancer patients, a main goal of the National Cancer Institute.

迫切需要开发针对恶性实体瘤的新疗法。肿瘤缺氧，减少在部分氧气中，压力是实体瘤生长的特征，并且在不足之后发展先前存在的脉管系统的氧气供应。这种现象通过激活刺激肿瘤进展允许肿瘤引起的血管生成和代谢适应生长的生理反应低氧环境。它也是癌细胞对放射和放射和抗性的主要因素化学治疗。缺氧会触发缺氧可耐受性因子1（HIF-1）的激活，这是转录因子驱动编码促血管生成因子和糖酵解酶的基因的转录，这些酶有助于肿瘤生长。通过HIF-1A敲除或淘汰方法抑制HIF-1功能的策略在包括胶质母细胞瘤（最恶性脑肿瘤）在内的实验模型中，肿瘤生长降低了目前没有有效的疗法。在这里，我们想检验以下假设抑制HIF-1途径的分子将抑制胶质母细胞瘤的生长，无论与其他代理商结合。我们已经开发了一种新型的潜在治疗剂的管道使用基于HIF-1响应的细胞筛选小分子化合物的天然产物样库记者测定法。我们已经生成了广泛的初步数据，表明两个结构类别的类别鉴定出的化合物在体外和体内具有有效的抗HIF活性。此外，我们发现我们的铅HIF抑制剂通过独特的机制起作用，并能够强烈抑制体内肿瘤生长系统性给药。我们计划进一步开发这些铅分子，在动物中进一步测试它们胶质母细胞瘤的模型作为依赖HIF-1激活的侵袭性瘤肿瘤的模型，以促进其生长，并确定其精确的作用机理。这些研究具有创新性，因为这些分子具有一种新颖的独特化学结构和作用机理，并且需要小分子的压力 HIF途径抑制剂。这些小分子作为大型候选治疗具有很大的潜力依靠HIF途径生长的实体瘤数量。这些临床前研究具有通过增加癌症患者的生存率直接使人类健康受益的潜力，这是一个主要目标国家癌症研究所。