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Indiana University Center for Pediatric Pharmacology and Precision Medicine

印第安纳大学儿科药理学和精准医学中心

基本信息

批准号：
9974297
负责人：
JAMIE L RENBARGER
金额：
$ 67.65万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974297
关键词：
Address Adverse drug effect Algorithms Amaze Applications Grants Area Biological Markers Cell Line Cessation of life Chemotherapy-Oncologic Procedure Child Child health care Childhood Childhood Cancer Treatment Clinical Data Development Disease Drug usage Ensure Europe Faculty Funding Future Generations Genome Genomics Glean Goals Hepatic Veno-Occlusive Disease Hepatotoxicity Indiana Individual Lead Leadership Learning Life Link Malignant Childhood Neoplasm Malignant Neoplasms Medicine Mission Molecular Molecular Analysis Outcome Outcomes Research Patients Pediatric Oncology Pharmaceutical Preparations Pharmacogenomics Pharmacology Pharmacotherapy Physicians Plasma Proteins Precision therapeutics Prevention Productivity Prognostic Marker Proteomics Records Recurrent disease Refractory Relapse Research Research Personnel Safety Savings Scientist Seasons Son of Sevenless Proteins Testing Therapeutic Toxic effect Toxicity due to chemotherapy Training Translating Treatment outcome Tumor Markers Universities Work Xenograft procedure anti-cancer base biomarker discovery chemotherapeutic agent childhood sarcoma cohesion experience genome sequencing hematopoietic cell transplantation high risk improved improved outcome innovation insight interest logarithm member mortality multidisciplinary novel novel strategies pediatric patients pediatric pharmacology personalized medicine precision medicine precision oncology predicting response predictive marker predictive signature randomized trial response side effect sound stem success transcriptomics treatment optimization tumor whole genome

项目摘要

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, 30% of children with cancer develop relapsed disease, the majority of whom die of their diseases. Furthermore, 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, transcriptomics, and proteomics, offer great hope to these patients in terms of improved therapeutic precision, safety, and efficacy. We propose to combine informed candidate genomics with targeted proteomics in our focused multifactorial approach in parallel with whole genome sequencing to translate and optimize therapeutics in children. Our overall hypothesis is that combinations of carefully selected biomarkers are associated with toxicity and overall response to pediatric cancer chemotherapy; and that using highly predictive biomarkers to guide therapy for individual children will result in improved outcomes. The objective of this center grant application is to identify the best combinations of biomarkers to predict response and toxicities and to evaluate the therapeutic benefit of treating children with life-threatening cancers who are at high risk for severe adverse drug effects. We propose two interdisciplinary and closely interlinked projects supported by our Administrative Core. Project I will test the hypothesis that using a precision medicine approach (incorporating focused NGS based tumor molecular characterization and targeted germline pharmacogenomics) in selecting individualized therapeutic strategies to relapsed and refractory pediatric sarcomas is superior to using a traditional approach. Project I will also evaluate therapeutic combinations for treatment of relapsed pediatric sarcomas informed by focused tumor molecular analysis using our own patient-derived cell lines and xenografts and will aim to discover novel targets to refine our precision medicine approach to improve outcomes in this deadly group of pediatric diseases. Project II will utilize a novel panel of plasma protein biomarkers prognostic of hematopoietic cell transplant (HCT) therapy-related sinusoidal obstruction syndrome in children as the basis of a randomized trial evaluating defibrotide (a drug approved in Europe for treatment of SOS) for prevention of this potentially fatal treatment-associated liver toxicity. This proposal will make a significant positive impact by providing critical information for physicians to make informed decisions for safer and more effective use of drugs in children. Furthermore, our application will ensure that both training and research, in pediatric and developmental pharmacology, remains at the forefront of the development and use of all medications in children. The direct outcome of these multidisciplinary studies will be discovery of new biomarkers and predictive signatures that will increase the precision of treatment for life-threatening childhood cancers and minimize severe treatment-associated side effects.

许多儿童癌症的治疗进展是一个惊人的成功故事。许多人的生存儿童恶性肿瘤在过去的三十年里有了显著的改善。然而，尽管有这些值得注意的是，30%的癌症儿童会复发，其中大多数死于癌症。疾病此外，许多化学治疗剂与显著的副作用相关，其可在某些情况下会使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、转录组学和蛋白质组学为这些患者提供了极大的希望，治疗精度、安全性和有效性。我们建议将联合收割机知情的候选基因组学与靶向蛋白质组学在我们集中的多因子方法中与全基因组测序并行，优化儿童的治疗方法。我们的总体假设是，与儿科癌症化疗的毒性和总体反应有关;并且使用高剂量的预测性生物标志物指导个别儿童的治疗将导致改善的结果。的目标该中心的拨款申请是为了确定生物标志物的最佳组合，以预测反应和毒性。并评估治疗患有危及生命的癌症的儿童的治疗益处，严重的药物不良反应。我们提出了两个跨学科和密切相关的项目，由我们的行政核心。项目一将测试假设，使用精确医学方法（包括聚焦基于NGS的肿瘤分子表征和靶向生殖系药物基因组学），复发性和难治性小儿肉瘤的个体化治疗策略上级使用传统的方法。项目I还将评估治疗复发性儿童通过使用我们自己的患者来源的细胞系进行集中的肿瘤分子分析，异种移植，并将旨在发现新的目标，以完善我们的精准医学方法，以改善这组致命的儿科疾病的结果。项目二将利用一种新的血浆蛋白质组造血细胞移植（HCT）治疗相关的肝窦阻塞综合征的生物标志物预后作为评价去纤维蛋白肽（一种在欧洲批准用于治疗 SOS）预防这种潜在致死性治疗相关肝毒性。这项提案将使通过为医生提供关键信息，为更安全的医疗保健做出明智的决定，更有效地使用药物。此外，我们的应用程序将确保培训和儿科和发育药理学研究仍然处于开发和使用的前沿，所有儿童用药。这些多学科研究的直接结果将是发现新的生物标志物和预测特征，将提高对危及生命的儿童的治疗精度癌症和最大限度地减少严重的治疗相关的副作用。