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

发现血管生成遗传决定因素的新模型及其影响

• 批准号: 8833259
• 负责人: FEDERICO INNOCENTI
• 金额: $ 19.84万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-07 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833259
• 关键词: Acute; Affect; Angiogenic Switch; BAY 54-9085; Behavior; Biological; Biological Assay; Biological Markers; Biological Models; Blood capillaries; Cancer Patient; Cell Line; Cell Survival; Cell model; Cellular Assay; Clinic; Clinical; Clinical Trials; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Foundations; Genes; Genetic; Genetic Determinism; Genetic Engineering; Genetic Markers; Genetic Variation; Genetic study; Goals; Growth; Growth and Development function; Health; Human; Individual; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modeling; Molecular; Molecular Genetics; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Positioning Attribute; Process; Property; Recurrent disease; Research; Risk; Role; Signal Pathway; Single Nucleotide Polymorphism; Staging; Survival Rate; System; Testing; Time; Tumor Angiogenesis; Tumor-Associated Vasculature; Vascular Endothelial Growth Factors; advanced disease; aggressive therapy; angiogenesis; base; bevacizumab; cancer therapy; capillary; inhibitor/antagonist; migration; novel; outcome forecast; research study; response; small molecule; tumor; tumor growth; tumor progression

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.

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。确定将通过一种疗法比另一种疗法获得更多益处的患者是一个重大挑战。遗传标记物已显示可用于预测患者药物反应，但对于许多药物（例如VEGF-Pathway抑制剂），目前没有有验证的标记来指导药物选择。 VEGF-Pathway抑制剂靶向并抑制肿瘤脉管系统的生长和相关的内皮。 VEGF-Pathway在血管生成中起着核心作用，已显示与癌症疾病进展有关。实际上，已经发现VEGF-Pathway中可遗传的遗传标记与包括肺癌在内的许多癌症中的患者结局相关。肺癌是一种癌症的病例模型，受肿瘤的血管生成潜力影响，并在诊所中使用了VEGF抑制剂并进行了实验评估。这项研究的总体目的是找到VEGF-Pathway遗传标记，可用于预测患者的预后或对VEGF-Pathway抑制剂药物的反应。一个主要问题是，研究VEGF-Pathway遗传标记和患者结局之间关联的研究通常尚无定论。这部分是由于缺乏对这些标记的血管生成功能知识的结果。因此，目前不能使用VEGF-Pathway的遗传标记来个性化癌症患者的治疗。拟议的研究将分析来自VEGF-Pathway的候选遗传标记，以确定它们是否具有影响肿瘤血管生成的功能和对VEGF-Pathway抑制剂的反应。人体内皮细胞将是基因工程的 从肺癌的先前VEGF-Pathway研究中选择的遗传标记。该模型系统将允许在检查与血管生成相关的内皮细胞特性的细胞测定中分离VEGF-Pathway遗传标记的作用。在这些测定中显示影响的遗传标志物将在实验中分析，在该实验中，用VEGF-Pathway抑制剂处理等源性内皮细胞。除细胞活力测定外，这些药物的抗血管生成作用将在与以前相同的细胞血管生成测定中检查，以确定细胞反应是否取决于存在的VEGF-pathway途径遗传标记。从这项研究中获得的信息可以大大推动并为VEGF途径遗传标记物的发展提供信息，以预测癌症结果和对VEGF-Pathway抑制剂的反应。可以在临床试验中对这些标记进行测试，以确定它们是否可以用来鉴定有早期疾病进展风险的癌症患者，这些患者可能会受益于更具侵略性的治疗或将从其他药物中受益于特定VEGF-Pathway抑制剂的患者。