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.

Public Health Relevance

The overall mission of the Indiana University Center for Pediatric Pharmacology and Precision Medicine application is the discovery of new biomarkers and predictive signatures that will improve treatment outcomes and minimize treatment-associated side effects in children with life-threatening childhood cancers. This proposal will make a significant positive impact by providing critical genome-directed information for physicians to make informed decisions for safer and more effective use of drugs in children.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD090215-04
Application #
9733316
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Ren, Zhaoxia
Project Start
2016-09-22
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Seo, Sachiko; Yu, Jeffrey; Jenkins, Isaac C et al. (2018) Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 24:678-686
Mounika Inavolu, S; Renbarger, J; Radovich, M et al. (2017) IODNE: An integrated optimization method for identifying the deregulated subnetwork for precision medicine in cancer. CPT Pharmacometrics Syst Pharmacol 6:168-176
Carter, J; Cheng, L; Zucker, J et al. (2017) Use of Precision Medicine Molecular Profiling of Baseline Tumor Specimen May Not Benefit Outcomes in Children With Relapsed or Refractory Pediatric Sarcomas. Clin Pharmacol Ther 101:328-330
Pandya, Pankita H; Fisher, Amanda J; Mickler, Elizabeth A et al. (2016) Hypoxia-Inducible Factor-1? Regulates CD55 in Airway Epithelium. Am J Respir Cell Mol Biol 55:889-898
Pandya, Pankita H; Murray, Mary E; Pollok, Karen E et al. (2016) The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches. J Immunol Res 2016:4273943