Indiana University Center for Pediatric Pharmacology

描述（由申请人提供）：许多儿童癌症的治疗进展是一个令人惊叹的成功故事。许多儿童恶性肿瘤的生存率在过去三十年中呈对数增长。然而，尽管取得了这些显著的进步，许多化疗药物都伴随着显著的副作用——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。我们建议将候选途径和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剂）结合起来，在我们专注的多因素方法中优化儿童治疗方法。我们假设精心选择的生物标志物组合与表型相关

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.