Targeting Glioblastoma Using Novel Small Molecule HIF-1 Pathway Inhibitors

描述（申请人提供）：恶性实体瘤迫切需要开发新的治疗方法。肿瘤缺氧，局部氧分压降低是实体瘤生长和发展的特征，是由于先前存在的血管供氧不足而发展的。这种现象通过激活生理反应刺激肿瘤进展，使肿瘤诱导的血管生成和代谢适应缺氧环境下的生长。它也是癌细胞对放疗和化疗产生耐药性的一个主要因素。缺氧触发缺氧诱导因子1 （HIF-1）的激活，HIF-1是一种转录因子，可驱动编码促血管生成因子和糖酵解酶的基因转录，促进肿瘤生长。通过HIF-抑制HIF-1功能的策略敲低或敲除方法已经减少了实验模型中的肿瘤生长，包括胶质母细胞瘤，这是目前尚无有效治疗方法的最恶性脑肿瘤。在这里，我们想验证一个假设，即抑制HIF-1通路的小分子会单独或与其他药物联合抑制胶质母细胞瘤的生长。我们通过hif -1应答细胞报告试验筛选天然产物样的小分子化合物库，开发了这种潜在治疗剂的新管道。我们已经生成了大量的初步数据，表明鉴定的两种结构类型的化合物在体外和体内具有有效的抗hif活性。此外，我们发现我们的先导HIF抑制剂通过一种独特的机制起作用，在全身给药后能够强烈抑制体内肿瘤的生长。在这里，我们计划进一步开发这些先导分子，在胶质母细胞瘤的动物模型中进一步测试它们，作为依赖HIF-1激活生长的侵袭性实体肿瘤的模型，并确定它们的确切作用机制。这些研究的创新之处在于这些分子具有新颖独特的化学结构和作用机制，迫切需要小分子HIF通路抑制剂。这些小分子具有作为大量依赖HIF途径生长的实体肿瘤的候选治疗药物的巨大潜力。这些临床前研究有可能通过提高癌症患者的生存率而直接造福人类健康，这是美国国家癌症研究所的一个主要目标。

DESCRIPTION (provided by applicant): 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-?? 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 aggressive solid 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.