A new model for discovering genetic determinants of angiogenesis and the effect o

描述(由申请人提供)：大多数癌症患者通常对某种药物没有反应。这是一个重大的挑战，以确定哪些患者将从一种疗法中获得比另一种疗法更多的好处。遗传标记已被证明在预测患者的药物反应方面是有用的，但对于许多药物，例如血管内皮生长因子途径抑制剂，目前还没有有效的标记来指导药物选择。血管内皮生长因子途径抑制物靶向并抑制肿瘤血管和相关内皮的生长。血管内皮生长因子途径在血管生成中起着核心作用，并已被证明与癌症疾病的进展有关。事实上，已经发现血管内皮生长因子途径中的可遗传遗传标记与包括肺癌在内的许多癌症的患者预后有关。肺癌是一种受肿瘤血管生成潜能影响的癌症的病例模型，目前正在临床和实验中对其使用血管内皮生长因子抑制剂。本研究的总体目的是寻找可用于预测癌症患者预后或对血管内皮生长因子途径抑制剂药物反应的血管内皮生长因子途径基因标记物。一个主要的问题是，研究血管内皮生长因子途径遗传标志物和患者预后之间的关系的研究往往是不确定的。这在一定程度上是由于缺乏对这些标记物的血管生成功能的了解。因此，目前还不能将血管内皮生长因子途径的遗传标记用于癌症患者的个体化治疗。这项拟议的研究将分析来自血管内皮生长因子途径的候选遗传标记，以确定它们是否具有影响肿瘤血管生成和对血管内皮生长因子途径抑制剂的反应的功能。人类内皮细胞将被基因工程改造，从而创造出同基因的细胞系，唯一不同的是 从先前对肺癌的血管内皮生长因子途径研究中选择的遗传标记。这个模型系统将允许在检测与血管生成相关的内皮细胞属性的细胞检测中分离出血管内皮生长因子途径遗传标记的作用。在这些检测中显示效果的遗传标记将在用血管内皮生长因子途径抑制剂处理同基因内皮细胞的实验中进行分析。这些药物的抗血管生成作用将与以前一样，除了细胞活力分析外，还将在相同的细胞血管生成实验中进行检测，以确定细胞反应是否依赖于存在的血管内皮生长因子途径遗传标记物。从这项研究中获得的信息可以极大地促进和促进血管内皮生长因子途径遗传标记作为癌症预后和对血管内皮生长因子途径抑制剂的反应的预测指标的发展。这些标记物可以在临床试验中进行测试，以确定它们是否可以用于识别有早期疾病进展风险的癌症患者，这些患者可能从更积极的治疗中受益，或者哪些患者将从特定的血管内皮生长因子途径抑制剂中受益，而不是其他药物。

DESCRIPTION (provided by applicant): A majority of cancer patients are often unresponsive to a given drug. It is a significant challenge to identify patients who would gain more benefit fro one therapy over another. Genetic markers have shown to be useful in predicting patient drug responses but for many drugs, for example the VEGF-pathway inhibitors, no validated markers to guide drug selection presently exist. VEGF-pathway inhibitors target and suppress the growth of tumor vasculature and the associated endothelium. The VEGF-pathway plays a central role in angiogenesis and has been shown to relate to cancer disease progression. Indeed, heritable genetic markers in the VEGF-pathway have been found to associate with patient outcomes in many cancers, including lung cancer. Lung cancer is a case model for a cancer which is affected by the angiogenic potential of a tumor and for which VEGF inhibitors are being used in the clinic and experimentally evaluated. The overall aim of this research is to find VEGF-pathway genetic markers which could be used to predict cancer patient prognosis or responses to VEGF-pathway inhibitor drugs. A major problem is that studies that examine associations between VEGF-pathway genetic markers and patient outcomes are often inconclusive. This is, in part, a consequence of a lack of knowledge about the angiogenic function of these markers. Thus, genetic markers of the VEGF-pathway cannot be used to individualize therapy in cancer patients at this time. The proposed research will analyze candidate genetic markers from the VEGF-pathway to determine whether they have function which would impact tumor angiogenesis and responses to VEGF-pathway inhibitors. Human endothelial cells will be genetically engineered so that isogenic cell lines are created, differing solely at the position of genetic markers selected from prior VEGF-pathway studies of lung cancer. This model system will allow the effects of VEGF-pathway genetic markers to be isolated in cellular assays that examine endothelial cellular properties relevant to angiogenesis. Genetic markers that show effects in these assays will be analyzed in experiments in which isogenic endothelial cells are treated with VEGF-pathway inhibitors. The anti-angiogenic effects of these drugs will be examined in the same cellular angiogenesis assays as before, in addition to cell viability assays, to determine whether the cellular responses are dependent on the VEGF- pathway genetic marker present. The information gained from this research could significantly advance and inform the development of VEGF- pathway genetic markers as predictors of cancer outcomes and responses to VEGF-pathway inhibitors. These markers could be tested in clinical trials to determine if they could be used to identify cancer patients at risk of early disease progression who might benefit from more aggressive therapy or patients who would receive benefit from a specific VEGF-pathway inhibitor over other drugs.