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.

Public Health Relevance

We propose to improve the treatment of children with cancer by identifying the best combinations of biomarkers to predict response to anticancer chemotherapeutic agents. This will allow creation of new dosing algorithms to optimize the treatment of this pediatric population.

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 #
5U54HD071598-04
Application #
8677907
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Zajicek, Anne
Project Start
2011-09-26
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Skiles, Jodi L; Chiang, ChienWei; Li, Claire H et al. (2018) CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer. Pediatr Blood Cancer 65:
Sierra Potchanant, Elizabeth A; Cerabona, Donna; Sater, Zahi Abdul et al. (2017) INPP5E Preserves Genomic Stability through Regulation of Mitosis. Mol Cell Biol 37:
Stark, Julie; Renbarger, Jamie; Slaven, James et al. (2017) Glutathione-S-transferase P1 may predispose children to a decline in pulmonary function after stem cell transplant. Pediatr Pulmonol 52:916-921
Taylor, Julia F; Ott, Mary A (2016) Fertility Preservation after a Cancer Diagnosis: A Systematic Review of Adolescents', Parents', and Providers' Perspectives, Experiences, and Preferences. J Pediatr Adolesc Gynecol 29:585-598
Akil, Ayman; Zhang, Qing; Mumaw, Christen L et al. (2015) Biomarkers for Diagnosis and Prognosis of Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 21:1739-45
McGuire, Jennifer L; Barrett, Jeffrey S; Vezina, Heather E et al. (2014) Adjuvant therapies for HIV-associated neurocognitive disorders. Ann Clin Transl Neurol 1:938-52
Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki et al. (2013) The tumor suppressor CDKN3 controls mitosis. J Cell Biol 201:997-1012
Hennessy, S; Flockhart, D A (2012) The need for translational research on drug-drug interactions. Clin Pharmacol Ther 91:771-3