Integrative discovery of treatments for high-risk neuroblastoma

Abstract

Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

Retinoic acid induces differentiation in neuroblastoma via ROR1 by modulating retinoic acid response elements

“…S1B ). In another dataset, GSE120920 ( 28 ), patient-derived xenograft cultures from two patients with high-risk, MYCN-amplified NB (NB-PDX2 and NB-PDX3), were treated with RA for 6 and 24 h and whole transcriptome analysis was performed via DRUG-Seq. Similarly, an increase in ROR1 mRNA in both cell cultures post-RA treatment was observed ( Fig.…”

“…ROR1 and Wnt5a expression data was retrieved in GEO2R using probe IDs 205805_s_at and 205990_s_at respectively. In dataset GSE120920 ( 28 ), patient-derived xenograft cultures were obtained from cerebral metastasis of a stage 4 neuroblastoma patient (NB-PDX2) and a primary tumor in the adrenal gland of a patient with stage 3 neuroblastoma (NB-PDX3). Both cell lines were MYCN amplified.…”

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

“…Fluorescently labeling graft cells with CellTrace Violet made assessing cell divisions in the 3-day treatment period possible, as the marker is inherited equally by daughter cells through several divisions. This methodology improves on commonly used proliferation assays assessing proliferative activity in a cell population only at a single time point [20,31]. Our data demonstrate that BCP-ALL cells find the pericardial cavity to be a more hospitable environment than the yolk sac.…”

“…The hypoxic conditions might explain why any BCP-ALL cells transplanted into the yolk sac survived. Our flow cytometric methods to assess total cell proliferation (CellTrace Violet) and viability (annexin V/7AAD) more accurately and independently quantify proliferation and viability in engrafted cells than the almost ubiquitously used microscopy-based methods applied to zebrafish xenograft models [ 20 , 31 , 33 , 34 , 35 , 36 , 37 ].…”

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

“…RNA profiling and GSEA For Figure 5B, we used RNA sequencing using the method in Almstedt et al (2020) to profile U3013MG and U3180MG cells after 6 hr treatment by bortezomib, marizomib and delanzomib at 10nM (n = 3 technical replicates for each treatment). Vehicle treated cells were used as replicates (n = 3 technical replicates).…”