In spite of major improvements in treating high-risk neuroblastoma (NB) over the past 2 decades, greater than 50% of recurrent high-risk NB patients still die of the disease. A critical challenge in developing new drugs for NB is the limited number of patients available for clinical trials. Preclinical models that represent the biological diversity (including drug resistance mechanisms) are needed for biological and preclinical therapeutic studies. The Children's Oncology Group (COG) NB committee has made providing patient samples to our laboratory a major priority, enabling us to establish 200 NB cell lines and a growing number (32 to date) of patient-derived xenografts (PDX) which are freely available to investigators world-wide via the COG Cell Line and Xenograft Repository (www.COGcell.org). To enhance the value of these NB preclinical models to the many labs utilizing them we propose to define the genomic landscape, gene expression profiles, and response to selected drugs in these models. Cell lines providing data that inform xenograft experiments would be a valuable resource and cell line xenografts are necessary for certain animal imaging experiments. We have established cell lines and PDXs from the same patient samples enabling a comparison of cell lines to cell line xenografts, and both to PDXs. Our hypotheses are: 1) A large well-characterized panel of cell lines and PDXs from patients encompassing the spectrum of high-risk NB biology after exposure to current therapies is essential for progress in developing novel therapeutics against recurrent disease. 2) Low-passage cell lines established in physiological hypoxia will yield drug response data both in vitro and as cell line xenografts that will be comparable to PDXs. The goals of this study are: 1) To characterize panels of NB in vitro and in vivo models, including isogenic pairs, (i.e. both cell line and PDX established from the same patient sample and also pairs established at diagnosis and from the same patient at disease progression) in terms of genomic landscape, genome-wide expression patterns (by RNA sequencing), expression of 200 selected proteins, and response to standard-of-care drugs. 2) To compare drug sensitivity to genomic alterations and genome-wide RNA expression to define molecular mechanisms of drug resistance. 3) To define the similarities or differences between cell line xenografts and PDXs using pairs of cell lines and PDXs established from the same clinical sample. 4) To compare the genomics of PDXs and cell lines to original patient tumor tissue and drug response data with PDXs and cell lines to clinical activity in patients of the same drugs. Our ultimate goal is to characterize a large robust panel of preclinical NB models for specific genomic abnormalities, genome-wide gene RNA expression and selected protein expression, and sensitivity/resistance to drugs commonly used for therapy and to ensure these models are readily available to all investigators studying neuroblastoma.
Our laboratory serves as the Children's Oncology Group (COG) Cell Line and Xenograft Repository, which provides laboratory models of childhood cancer to investigators across the USA and in 20 countries. One of the largest panel of models we have in the COG repository is from the childhood cancer neuroblastoma and we propose to greatly expand the data available on the large panel of neuroblastoma cell lines and tumors growing in mice (patient-derived xenografts = PDX). This project will benefit many investigators carrying out neuroblastoma biological and preclinical therapeutic research and ultimately will benefit neuroblastoma patients by enhancing the quality of laboratory models available for new drug development and identifying models manifesting defined molecular mechanisms of drug resistance.
