Indiana University Center for Pediatric Pharmacology

描述(申请人提供)：许多儿童癌症的治疗进展是一个令人惊叹的成功故事。在过去的三十年里，许多儿童恶性肿瘤的存活率呈对数增长。然而，尽管取得了这些显著的进展，许多化疗药物都有明显的副作用--在某些情况下，这些副作用可能会使人虚弱，甚至危及生命。生物标记物发现的进展，包括基因组学、药物基因组学和蛋白质组学，为这些患者在提高治疗精确度、安全性和有效性方面带来了巨大的希望。我们建议将候选途径和知情候选变异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)相结合，在我们专注的多因素方法中优化儿童的治疗。我们假设，精心挑选的生物标志物的组合与表型有关 儿童癌症化疗毒性和总体反应的标记物。这项中心拨款申请的目标是确定预测抗癌反应的生物标记物的最佳组合 儿童的化疗药物。我们提出了三个多学科和密切相关的项目 由我们的行政、生物统计和建模核心提供支持。项目I将在两个儿科患者群体中测试生物标记物的组合与长春新碱神经毒性和药代动力学仔细定义的措施相关的假设。项目二将使用靶向蛋白质组学和信息基因组学来测试生物标记物的组合是否能够在观察性试验中最佳地预测与造血干细胞移植(HSCT)治疗相关的儿童窦性梗阻综合征的风险。项目111将评估血管生成的循环细胞标记物和集中的血管内皮生长因子途径遗传学是否与1)项目I的实体肿瘤患者的治疗效果和2)项目II的HSCT患者的SOS风险有关。这些研究的直接结果将是新的生物标记物和预测性特征，将提高现有剂量方案用于儿童癌症治疗的精确度。

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.