In vitro and in vivo drug screens of tumor cells identify novel therapies for high‐risk child cancer

Abstract

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid highthroughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

“…Recently, the first results of the TARGET pilot study of the Australian ZERO Precision Childhood Cancer Program have been published by Lau and colleagues 28 . Similar to our study, pediatric patients with high-risk poor prognosis cancer were enrolled, covering a broad spectrum of pediatric solid and brain tumors.…”

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

“…This is a retrospective analysis of the tumour immune microenvironment from 347 patient samples that were obtained as part of the Australian ZERO Childhood Cancer Precision Medicine Program consisting of the TARGET and PRISM clinical trials. The TARGET pilot study recruited patients from the two children’s hospitals in Sydney (Sydney Children’s Hospital, Randwick, and the Children’s Hospital at Westmead), Australia, from June 2015 to October 2017 and was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee (LNR/14/SCH/497), with the results of the pilot study already published [ 29 ] . The PRISM clinical trial (NCT03336931) data for this analysis was collected from September 2017 to August 2020 at all eight paediatric oncology centres around Australia (Sydney Children’s Hospital, Randwick; the Children’s Hospital at Westmead, Sydney; Queensland Children’s Hospital, Brisbane; Perth Children’s Hospital, Perth; Women’s & Children’s Hospital, Adelaide; John Hunter Hospital, Newcastle; Royal Children’s Hospital, Melbourne; and Monash Children’s Hospital, Melbourne) and was approved by the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (reference no.…”

Patient-derived models: Advanced tools for precision medicine in neuroblastoma

“…Nevertheless, the rarity of pediatric cancers and scarcity of models representing specific subtypes within pediatric tumors makes those repositories a valuable resource for the accelerated development and translation of novel therapeutics into early phase trials (34,111,112). Lau et al developed a pediatric precision medicine platform (including a few high-risk NBs) of PDX models and HTS in PDOs, observing a correlation between PDX results, HTS-PDOs, and the clinical responses in patients (113). Importantly, the addition of functional drug testing to a genome-only analysis increased the number of patients with drug options by also identifying drug sensitivities not associated with molecular hallmarks (113).…”

“…Lau et al. developed a pediatric precision medicine platform (including a few high-risk NBs) of PDX models and HTS in PDOs, observing a correlation between PDX results, HTS-PDOs, and the clinical responses in patients ( 113 ). Importantly, the addition of functional drug testing to a genome-only analysis increased the number of patients with drug options by also identifying drug sensitivities not associated with molecular hallmarks ( 113 ).…”