15B. Liquid biopsies for precision medicine
Patients with high risk neuroblastoma, still have a 40% 3yr OS. Neuroblastoma is a heterogenous disease, and within the high risk phenotype several distinct molecular architecture are grouped, which probably underly the clinical risk groups in high-risk NB patients. These differences in tumour biology, phenotype and genotype, might possibly explain why 15% of children on frontline clinical-trials, which remain molecularly uneducated and lack mechanistically-targeted drugs, fail initial treatment or frequently relapse.
We propose that future clinical trials should implement standardised molecular-testing to improve diagnostic accuracy, identify patients likely to fail general therapy, and guide the use of molecularly-targeted treatments.
Liquid-biopsy is a form of blood- testing using technologies that can be used clinically, to detect, at-scale and in real-time, multiple molecular changes in tumour DNA released into blood (circulating tumour-derived DNA, ctDNA). Furthermore, different phenotypes such as Mesenchymal neuroblastoma, believed to play a role in resistance to therapy, can be discovered by a neuroblastoma-specific MES mRNA panel, or potentially by single cell (imaging) approaches.
In this proposal we describe how we will: 1) study the use of cfDNA as biomarker for targeted therapy, 2) evaluate the potential to detect mesenchymal neuroblastoma and correlate this with outcome, 3) develop liquid biopsy approaches to telomere maintenance mechanisms (TMMs) and IND (indolent) neuroblastoma in blood and 4) study the possibility that development of chemorefractory disease (and a MES state) could be detected by ctDNA-ChipSeq in patients on treatment in blood and bone-marrow samples.
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