Indiana University Center for Pediatric Pharmacology

印第安纳大学儿科药理学中心

• 批准号: 8677907
• 负责人: DAVID Alastair FLOCKHART
• 金额: $ 73.77万
• 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/8677907
• 关键词: Accounting; Acute Lymphocytic Leukemia; Address; Adult; Adverse drug effect; Adverse effects; Age; Algorithms; Amaze; Applications Grants; Area; Biological Markers; Biology; Biometry; Blood Vessels; Cell Count; Cellular biology; Chemotherapy-Oncologic Procedure; Child; Child Development; Childhood; Childhood Cancer Treatment; Childhood Injury; Childhood Solid Neoplasm; Clinical; Clinical Investigator; Clinical Pharmacology; Clinical Research; Complex; Confidentiality; Core Facility; Data; Data Set; Databases; Development; Disease; Disease Marker; Doctor of Philosophy; Dose; Dose-Limiting; Drug Exposure; Drug Interactions; Drug Kinetics; Drug toxicity; Endothelial Cells; Enrollment; Ensure; Environment; Enzymes; Equation; Evaluation; Focus Groups; Foundations; Fractals; Funding; Genes; Genetic; Genomics; Genotype; Germ Lines; Goals; Growth; Guidelines; Hematopoiesis; Hematopoietic stem cells; Hepatic; Hepatic Veno-Occlusive Disease; Hepatotoxicity; Human; Indiana; Individual; Informatics; Injury; Institutes; Kenya; Lead; Leadership; Letters; Life; Link; Liver Microsomes; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medicine; Metabolism; Michigan; Modeling; Multicenter Trials; Nature; Neuropathy; Online Systems; Ontology; Outcome; Outcome Study; Pathway interactions; Patient Care; Patients; Pediatric Hospitals; Pediatric Oncology; Pediatric Research; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Physiological; Plasma Proteins; Play; Population; Population Sciences; Positioning Attribute; Process; Proteomics; Publications; Recovery; Research; Research Infrastructure; Research Personnel; Research Project Grants; Risk; Role; Safety; Scientist; Seasons; Secure; Severities; Solid Neoplasm; Stem cell transplant; Stem cells; Technology; Testing; Therapeutic; Time; TimeLine; Toxic effect; Toxicity due to chemotherapy; Translational Research; Transplant Recipients; Treatment Efficacy; United States; United States National Institutes of Health; Universities; Variant; Vascular Endothelial Growth Factors; Vinca Alkaloids; Vincristine; Weight; Work; age effect; angiogenesis; base; cancer therapy; case control; cell injury; chemotherapeutic agent; chemotherapy; clinical decision-making; clinically relevant; control trial; data integration; data integrity; data management; drug metabolism; experience; genetic variant; high risk; improved; innovation; interest; leukemia; multidisciplinary; neurotoxicity; new technology; patient population; pediatric department; pediatric pharmacology; pediatrician; practical application; programs; repaired; response; stem; success; systems research; tool; tumor; tumor growth

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.

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。在过去三十年中，许多儿童恶性肿瘤的生存率呈对数增长。然而，尽管取得了这些显着的进步，许多化疗药物仍伴随着显着的副作用——在某些情况下可能会让人衰弱，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）结合起来，在我们重点关注的多因素方法中优化儿童治疗。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来预测抗癌反应 儿童化疗药物。我们提出三个多学科且紧密相连的项目 由我们的管理和生物统计以及建模核心提供支持。项目 I 将测试以下假设：生物标志物组合与两个儿科患者群体中仔细定义的长春新碱神经毒性和药代动力学测量相关。项目 II 将使用靶向蛋白质组学和知情基因组学来测试生物标志物组合是否能够在观察性试验中最佳预测儿童造血干细胞移植 (HSCT) 治疗相关的血窦阻塞综合征的风险。项目 111 将评估血管生成的循环细胞标记物和聚焦的血管内皮生长因子通路遗传学是否与 1) 项目 I 的实体瘤患者的治疗效果和 2) 项目 II 的 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剂量方案的精度。