Children's Oncology Group (COG) Translational Research Committee Core Laboratory
(Genome-wide Screening for Therapeutic Targets in Childhood Cancer)

PI: Gregory Reaman, M.D.
National Childhood Cancer Foundation

USAMRMC NUMBER: 0621300

ABSTRACT

Background: Identifying molecular mechanisms of malignant transformation that can be specifically targeted can lead to more effective and less toxic cancer treatments. Numerous lines of experimental evidence support genome-wide approaches to defining transcriptional RNA patterns, DNA structural changes, epigenetic methylation changes and functional pathway screening. Each of these critical areas is known to be altered in cancer, providing potentially specific or selective pathways for therapeutic targeting.

Objective/Hypothesis: The central hypothesis is that detailed mapping of transcription, DNA structural changes, DNA copy number, genomic methylation and functional pathways will show important similarities and differences among pediatric high-risk sarcomas and AML that can be used to predict outcome, direct therapy and identify new therapeutic targets.

Specific Aims: For each tumor type and subtype we propose to 1) determine genome-wide transcriptional profiles; 2) provide detailed genome methylation patterns and 3) identify functional pathways that involve tumor cell survival and drug sensitivity.

Study Design: Tissue samples, cell lines, and xenografts from high-risk sarcomas and leukemia will be obtained from COG repositories and used to determine transcriptional profiles and genomic methylation patterns using novel, genome-wide, high-density microarray approaches along with siRNA screening to identify functionally important pathways. A preclinical core will conduct preclinical drug testing and a biostatistical core will integrate the extensive data sets to define critical genes and pathways for therapeutic targeting.

Relevance: The proposed studies will significantly advance the application of genome-wide mapping of pediatric cancers but also generate data and methods directly applicable to adult cancers and other genetic disorders.

The research is divided into 3 main research projects which are supported by 3 cores:

Project 1) Transcriptional and Mutation Profiling
PI: Timothy J. Triche, MD PhD
Childrens Hospital Los Angeles and
Keck School of Medicine Univ of Southern California

Project 2) Genomic Methylation Patterns
PI: Robert J. Arceci, MD, PhD
Kimmel Comprehensive Cancer Center at Johns Hopkins

Project 3) siRNA Pathway Inhibition
PI: Poul HB Sorensen, MD, PhD
University of British Columbia
Senior Scientist, BC Cancer Research Centre

Preclinical Core
Co-PI: Markus Warmuth, PhD
Novartis Foundation

Co-PI: C Patrick Reynolds, MD PhD
Childrens Hospital Los Angeles and
Keck School of Medicine Univ of Southern California

Biostatistical Core
PI: Jonathan Buckley, MD PhD
Keck School of Medicine Univ of Southern California

Administrative Core
PI: Gregory Reaman, MD
Administration: Albert Roy
Children's Oncology Group