Indiana University Center for Pediatric Pharmacology

印第安纳大学儿科药理学中心

• 批准号: 8246593
• 负责人: DAVID Alastair FLOCKHART
• 金额: $ 78.73万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246593
• 关键词: Indiana; University; Center; Pediatric; Pharmacology

DESCRIPTION (provided by applicant): The progress in the treatment of many childhood cancers is a story of amazing successes. Survival for many childhood malignancies has improved logarithmically over the past three decades. However, despite these remarkable advances, many chemotherapeutic agents are associated with significant side effects-which can be debilitating and even life threatening in some cases. Advances in biomarker discovery, including genomics, pharmacogenomics, and proteomics, offer great hope to these patients in terms of improved therapeutic precision, safety, and efficacy. We propose to combine candidate pathway and informed candidate variant genomics with targeted proteomics, and circulating endothelial progenitor cell subsets (a cellular regulator of angiogenesis) in our focused multifactorial approach to optimized therapeutics in children. We hypothesize that combinations of carefully selected biomarkers are associated with phenotypic markers of toxicity and overall response to pediatric cancer chemotherapy. The objective of this center grant application is to identify the best combinations of biomarkers to predict response to anticancer chemotherapeutic agents in children. We propose three multidisciplinary and closely interlinked projects supported by our Administrative and Biostatistics and Modeling Cores. Project I will test the hypothesis that combinations of biomarkers are associated with carefully defined measures of vincristine neurotoxicity and pharmacokinetics in two pediatric patient populations. Project II wil use targeted proteomics and informed genomics to test whether a combination of biomarkers will be able to optimally predict the risk of hematopoietic stem cell transplant (HSCT) therapy-related sinusoidal obstruction syndrome in children in an observational trial. Project 111 will evaluate whether circulating cellular markers of angiogenesis and focused vascular endothelial growth factor pathway genetics are associated with 1) treatment efficacy in the solid tumor patients from project I and 2) risk of SOS in the HSCT patients from project II. The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. PUBLIC HEALTH RELEVANCE: We propose to improve the treatment of children with cancer by identifying the best combinations of biomarkers to predict response to anticancer chemotherapeutic agents. This will allow creation of new dosing algorithms to optimize the treatment of this pediatric population.

描述（由申请人提供）：许多儿童癌症的治疗进展是一个惊人的成功故事。在过去的三十年里，许多儿童恶性肿瘤的生存率有了很大的提高。然而，尽管有这些显著的进步，许多化疗药物与显着的副作用，这可能是衰弱，甚至在某些情况下危及生命。生物标志物发现的进展，包括基因组学、药物基因组学和蛋白质组学，在提高治疗精度、安全性和有效性方面为这些患者带来了巨大的希望。我们建议将联合收割机候选途径和知情的候选变体基因组学与靶向蛋白质组学和循环内皮祖细胞亚群（血管生成的细胞调节因子）结合起来，采用集中的多因素方法来优化儿童治疗方法。我们假设精心选择的生物标志物的组合与表型相关， 毒性标志物和对儿科癌症化疗的总体反应。该中心拨款申请的目的是确定生物标志物的最佳组合，以预测抗癌药物的反应。 儿童化疗药物。我们提出三个多学科和密切相关的项目 由我们的行政和生物统计和建模核心支持。项目I将在两个儿科患者人群中检验生物标志物组合与长春新碱神经毒性和药代动力学的仔细定义指标相关的假设。项目II将在一项观察性试验中使用靶向蛋白质组学和知情基因组学来测试生物标志物的组合是否能够最佳地预测儿童造血干细胞移植（HSCT）治疗相关的窦阻塞综合征的风险。项目111将评价血管生成的循环细胞标志物和聚焦血管内皮生长因子通路遗传学是否与1）项目I中实体瘤患者的治疗疗效和2）项目II中HSCT患者的SOS风险相关。这些研究的直接结果将是新的生物标志物和预测特征，这将提高用于治疗儿童癌症的现有给药方案的精确度。 公共卫生关系：我们建议通过确定生物标志物的最佳组合来预测对抗癌化疗药物的反应，从而改善儿童癌症的治疗。这将允许创建新的给药算法，以优化该儿科人群的治疗。