Molecular targets of hypoxia in signaling cancer

描述(由申请人提供)：有令人信服的证据表明，肿瘤血管生成是肿瘤生长超过最小尺寸所必需的。肿瘤细胞分泌的血管生成多肽诱导新血管生长进入肿瘤。产生这些血管生成因子的刺激因素是肿瘤缺氧，特定的癌基因和肿瘤抑制基因的突变加剧了这种刺激。低氧诱导转录因子(HIF)是这种细胞对低氧反应的中心调节因子，也是几种血管生成因子的上游激活物。 Von Hippei-Lindau(VHL)病是HIF被解除调控的典型疾病。VHL功能的丧失直接稳定HIF，并通过促进肿瘤细胞的增殖而导致与恶性表型有关的基因的反式激活。 HIF可能是VHL+/+和VHL-/-实体瘤生长所必需的。因此，可以想象，抑制HIF，而不是单独针对每个特定的血管生成因子，可能是抑制和/或防止肿瘤形成的有效策略。 在目标1中，我们建议从肿瘤细胞系中获得稳定和可诱导的克隆，其中HIF活性通过表达短干扰RNA而被抑制。作为第二个策略(目标1和2)，我们将使用我们在高通量筛选中发现的小分子HIF抑制剂。我们将确定抑制VHL+/+和VHL-/-肿瘤细胞系的分子机制以及这些化合物对VHL+/+和VHL-/-肿瘤细胞系促血管生成的影响。药物引导的给药方案将用于研究抑制剂对小鼠移植和自发发展的肿瘤的影响。这些研究将测试HIF是否对肿瘤血管生成是必要的。在这些原理验证实验过程中产生的试剂可能为抗癌药物的开发提供直接依据。

DESCRIPTION (provided by applicant): There is compelling evidence that tumor angiogenesis is necessary for a tumor to grow beyond a minimal size. Tumor cell secreted angiogenic peptides induce the growth of new blood vessels into tumors. The stimulus for the production of these angiogenic factors is tumor hypoxia and it is accentuated by mutations in specific oncogenes and tumor suppressor genes. The Hypoxia Inducible transcription Factor (HIF) is a central regulator of this cellular response to hypoxia and an upstream activator of several angiogenic factors. A prototypic disorder in which HIF is deregulated is Von HippeI-Lindau (VHL) disease. Loss-of-VHL function directly stabilizes HIF and results in the transactivation of genes contributing to the malignant phenotype by promoting tumor cell proliferation. HIF may be necessary for growth of VHL+/+ and VHL-/- solid tumors. It is, therefore, conceivable that inhibiting HIF, instead of targeting each specific angiogenic factor separately, may be a powerful strategy to inhibit and/or prevent tumor formation. In Aim 1 we propose to generate stable and inducible clones derived from tumor cell lines, in which HIF activity is inhibited through expression of short interfering RNA. As a second strategy (Aims 1 and 2) we will use small molecule HIF inhibitors that we discovered in a high throughput screen. We will determine the molecular mechanism of inhibition and the effect of these compounds on the overall pro-angiogenic profile of VHL+/+ and VHL-/- tumor cell lines. Pharmacologically guided dosing regimens will be used to study the effect of inhibitors on xenografted and spontaneously developing tumors in mice. These studies will test whether HIF is necessary for tumor angiogenesis. Reagents generated at the course of these proof-of-principle experiments may provide the direct basis for anti-cancer drug development.