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.

许多童年癌症治疗的进展是一个惊人的成功的故事。许多人的生存在过去的三十年中，儿童恶性肿瘤在对数方面有所改善。但是，这些显着的进步，有30％的癌症患者患有继电器疾病，其中大多数死于他们的疾病疾病。此外，许多化学治疗剂与重大副作用相关 - 在某些情况下，使人衰弱甚至威胁生命。生物标志物发现的进步，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巨大的希望。治疗精度，安全性和效率。我们建议将知情的候选基因组学与有针对性的与整个基因组测序平行地翻译和优化儿童的治疗。我们的总体假设是精心选择的生物标志物的组合与毒性和对小儿癌化疗的总体反应有关；而且使用高度指导个别儿童治疗的预测生物标志物将改善结果。目的该中心赠款的应用是确定生物标志物的最佳组合，以预测响应和战术并评估患有威胁生命的癌症儿童的治疗益处严重的不良药物影响。我们提出了两个跨学科和密切相互联系的项目行政核心。项目我将测试以下假设：使用精确医学方法（合并）基于焦点NGS的肿瘤分子表征和靶向种系药物学）选择传达和难治性小儿肉瘤的个性化治疗策略优于使用传统方法。项目我还将评估治疗复发小儿的治疗组合肉瘤通过我们自己的患者衍生的细胞系进行了聚焦肿瘤分子分析，并异种移植物，旨在发现新的目标，以完善我们的精确医学方法以改进这一致命的小儿疾病的结果。项目II将利用一个新型的等离子体蛋白造血细胞移植（HCT）治疗相关正弦反对综合征的生物标志物预后在儿童中，作为评估除纤维肽的随机试验的基础（欧洲批准的药物用于治疗 SOS）预防这种潜在的致命治疗相关肝毒性。该建议将成为通过为医生提供关键信息，以为更安全做出明智的决定，从而产生重大积极影响并在儿童中更有效地使用毒品。此外，我们的应用程序将确保培训和在儿科和发展药理学方面的研究仍然处于开发和使用的最前沿在儿童的所有药物中。这些多学科研究的直接结果将是新的生物标志物和预测签名将提高威胁生命的儿童治疗精度癌症并最小化严重的治疗相关副作用。