Targeting Glioblastoma Using Novel Small Molecule HIF-1 Pathway Inhibitors

描述（由申请人提供）：迫切需要开发用于恶性实体瘤的新疗法。肿瘤缺氧，即氧分压的降低是实体瘤生长的特征，并且在来自预先存在的脉管系统的氧气供应不足之后发展。这种现象通过激活生理反应来刺激肿瘤进展，从而允许肿瘤诱导的血管生成和代谢适应缺氧环境下的生长。它也是癌细胞对放射疗法和化学疗法的抗性的主要因素。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，驱动编码促血管生成因子和糖酵解酶的基因转录，有助于肿瘤生长。通过HIF-1抑制HIF-1功能的策略？敲除或敲除方法在实验模型中减少了肿瘤生长，包括胶质母细胞瘤，胶质母细胞瘤是目前没有有效治疗的最恶性的脑肿瘤。在这里，我们想测试的假设，抑制HIF-1通路的小分子将抑制胶质母细胞瘤的生长，无论是单独或与其他药物组合。我们已经开发了一种新的管道，这样的潜在的治疗药物，通过筛选一个天然产物样库的小分子化合物，使用HIF-1-响应细胞为基础的报告分析。我们已经产生了大量的初步数据表明，两种结构类型的化合物鉴定具有有效的抗HIF活性，在体外和体内。此外，我们发现我们的主要HIF抑制剂通过独特的机制起作用，并且在全身给药后能够强烈抑制体内肿瘤生长。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瘤模型，并确定它们的精确作用机制。这些研究具有创新性，因为这些分子具有新颖独特的化学结构和作用机制，并且迫切需要小分子HIF通路抑制剂。这些小分子具有巨大的潜力，作为大量实体肿瘤的候选治疗剂，这些实体肿瘤依赖于HIF途径生长。这些临床前研究有可能通过增加癌症患者的生存率直接造福人类健康，这是美国国家癌症研究所的主要目标。

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.