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给定药物无反应。确定一种治疗比另一种治疗获益更多的患者是一个重大挑战。遗传标记已被证明在预测患者药物反应方面很有用，但对于许多药物，例如VEGF途径抑制剂，目前还没有经过验证的标记来指导药物选择。VEGF通路抑制剂靶向并抑制肿瘤血管系统和相关内皮的生长。VEGF通路在血管生成中起着重要作用，并已被证明与癌症疾病进展有关。事实上，已经发现VEGF通路中的遗传遗传标记与许多癌症（包括肺癌）的患者结局相关。肺癌是受肿瘤的血管生成潜力影响的癌症的病例模型，并且VEGF抑制剂正用于临床和实验评估。本研究的总体目标是寻找VEGF通路的遗传标记，可用于预测癌症患者的预后或对VEGF通路抑制剂药物的反应。一个主要的问题是，研究VEGF途径遗传标记和患者预后之间的关联往往是不确定的。这在一定程度上是由于缺乏对这些标志物的血管生成功能的了解。因此，VEGF通路的遗传标记目前不能用于癌症患者的个体化治疗。这项研究将分析VEGF通路的候选遗传标记，以确定它们是否具有影响肿瘤血管生成和对VEGF通路抑制剂反应的功能。人内皮细胞将被基因工程化，从而产生等基因细胞系，仅在以下位置不同： 从先前的肺癌VEGF通路研究中选择的遗传标记。该模型系统将允许VEGF途径遗传标记物的作用在检查与血管生成相关的内皮细胞特性的细胞测定中被分离。将在用VEGF通路抑制剂处理同基因内皮细胞的实验中分析在这些测定中显示效果的遗传标记物。除了细胞活力测定外，将在与之前相同的细胞血管生成测定中检查这些药物的抗血管生成作用，以确定细胞应答是否依赖于存在的VEGF途径遗传标记。从这项研究中获得的信息可以显着推进和告知VEGF途径遗传标记物的发展，作为癌症结局和对VEGF途径抑制剂反应的预测因子。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可能从更积极的治疗中受益的早期疾病进展风险的癌症患者，或者从特定的VEGF通路抑制剂中获益的患者。

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.