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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取得了惊人的成功。许多人的生存