Neuroblastoma (NB) remains a deadly disease for 60% of high-risk patients. Existing molecular classifiers/drug targets stem from single biopsies of bulky tumors, but this simplified view of NB homogeneity is inappropriate. Intratumor heterogeneity (ITH) must be taken into account for predictive biomarker identification.
ONTHETRRAC has assembled an international expert team in NB molecular genetics and clinical research, and build on their recent discoveries that NBs are both spatially and temporally heterogeneous, including intratumor, primary tumor/distant metastasis and diagnosis/relapse comparisons.
We will invest cutting-edge omics and liquid biopsy technologies to develop strategies overcoming ITH-based sampling inaccuracy and support in-depth predictive biomarker analyses. Clonal evolution and disease progression simulated in mouse and zebrafish models will support biomarker validation.
ONTHETRRAC aims to provide clinically relevant recommendations for how to molecularly diagnose and monitor disease course on the sub(clonal) level, taking spatial and temporal ITH into account. The resulting diagnostics and monitoring guidelines will be most valuable to guide new targeted therapeutic interventions and will directly be integrated into the next European high-risk and relapse NB trial protocols by partners participating in SIOPEN and GPOH trial planning boards, covering 99% of high-risk NB patients treated in Europe.
ONTHETRRAC has the power to generate a more complete picture of spatial/temporal ITH, thereby supporting individualized therapeutic strategies targeted to the most aggressive and resistant tumor clone. Minimally invasive techniques will improve the feasibility of monitoring mutations and disease load during treatment. We propose a highly innovative approach for the scientific foundation necessary for a paradigm shift from diagnostic single-biopsy use towards multiple tumor and liquid biopsies for NB clinical care.