Funding
Tour de Cure (TDC)
Australian Government (Federal Government)
New South Wales State Government
Australian Cancer Research Foundation (ACRF)
Cancer Therapeutics Cooperative Research Centre (Cancer Therapeutics CRC)
Cure Brain Cancer Foundation (CBCF)
Robert Connor Dawes Foundation (RCD)
Samuel Nissen Charitable Foundation
Luminesce Alliance
Medical Research Future Fund - Australian Brain Cancer Mission
Minderoo Foundation's Collaborate Against Cancer Initiative
National Health and Medical Research Council (NHMRC)
Funds raised through the Zero Childhood Cancer Capacity Campaign
Cancer Institute NSW (Cancer Institute New South Wales)
Neuroblastoma Australia
Steven Walter Children's Cancer Foundation
The Hyundai Help 4 Kids Foundation
ARTICLE ABSTRACT
For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers.
Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.
