The diagnosis of a pediatric solid tumor currently requires a tissue biopsy, which is an invasive procedure that is not able to capture the heterogeneity present within the entire tumor. These children then typically receive a combination of therapies, with response determined by serial imaging. This approach is complicated by exposure to radiation during imaging and requirements for sedation in younger children. Therefore, superior methods are needed for diagnosis and for monitoring of response to treatment in children with solid tumors. Recently, several technologies have been developed to analyze blood samples for the genomic presence of solid tumors within circulating free DNA or circulating tumor cells. However, their clinical utility is limited in pediatric neoplasms, which often rely on the detection of fusion transcripts for diagnosis. Exosomes, which are small, membrane-enclosed vesicles released from cells, contain mRNA, miRNA, and protein cargo unique to their cell of origin. Importantly, exosomes protect RNA from degradation and could provide the ideal biomarker for diagnosis, monitoring treatment response, and detection of early recurrence in children with solid tumors. However, further evaluation of the methods utilized for exosome isolation and cargo evaluation are needed to ensure that detection is reliable and reproducible prior to moving forward with the use of exosomes as biomarkers in the clinical realm. The proposed studies will identify the appropriate pre-analytic conditions for the reliable isolation of exosomes from the blood of pediatric patients with solid tumors containing known fusion transcripts identified through routine diagnostic testing, including Ewing Sarcoma/PNET, synovial sarcoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor, as well as for the reproducible detection of tumor-specific markers within the isolated exosomes. We will isolate exosomes from peripheral blood samples from a total of 50 healthy children and 30 children with newly diagnosed solid tumors during this study, and will apply clinical laboratory validation concepts of accuracy, precision, and analytic sensitivity and specificity to establish the reliability and utility of exosomal cargo as biomarkers in children with solid tumors. The overall goal of this study is to provide sufficient information to allow for the proposal of studies within the Children?s Oncology Group cooperative clinical trials to investigate the utility of exosome isolation and cargo analysis. We anticipate that within 10 years, the analysis of peripheral blood for exosome characteristics may provide a non-invasive method for establishing the diagnosis, monitoring treatment response, and detecting early recurrence in children with solid tumors.

Public Health Relevance

This study will investigate the use of exosomes (small, membrane-bound vesicles released from tumor cells) as markers in the blood of children with solid tumors to aid in diagnosis, monitoring treatment response, and detecting early recurrence of the tumor. This is significant for two reasons; first, it would provide a non-invasive method for monitoring children with solid tumors, decreasing the need for multiple tumor biopsies and frequent imaging scans. Second, exosomes may allow a more complete evaluation of the genetic changes that are associated with a child?s tumor, potentially allowing new treatment approaches in the future.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Biomarkers Study Section (CBSS)
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Children's Memorial Hospital (Chicago)
United States
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