Ultra-high-risk pediatric cancer - combinatorial drivers and therapeutic targets for precision medicine.
Project Coordinator: Dr. Sabine Taschner-Mandl (PhD), Children´s Cancer Research Institute/Solid Tumours
CCRI/Studies & Statistics for Integrated Research and Projects (S²IRP) St. Anna Children´s Hospital, AUT
CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, AUT
Ultra-high-risk (UHR) cancer patients are frequently ill-served by classical treatment options such as combination chemotherapy, but also require therapies focused on specific (epi-)genetic targets. This is often hampered by a lack of knowledge of the driver genes affected by large structural aberrations. We have identified UHR patients within the European high-risk neuroblastoma trial cohort (CCRI/St. Anna Children’s Hospital). Preliminary genomic analyses of UHR patients demonstrated that lack of treatment response and reduced survival are driven by loss-of-function mutations in ATRX and/or frequently co-occuring losses of chromosome arms indicating risk-relevant genes in these regions. We propose to (1) identify genes that drive the UHR phenotype by a CRISPR knock-out screen combined with single cell RNA-sequencing (CROP-seq), followed by thorough molecular validation in patient samples and functional validation in zebrafish xenografts. (2) Based on the identified genes we will perform a genome-wide screen for synthetically lethal genes and aided by computational models prioritize and test potentially synthetic lethal compounds. (3) Finally, we will pilot the first real-time functional drug testing on patient-derived xenograft zebrafish to enable personalized treatment recommendations for UHR patients.
Altogether, this strategy will provide clinical decision makers with a solid rationale to integrate the identified drugs in the clinic.
Funded under the programme Life Sciences 2018, Linking Research and Patients' Needs by the Vienna Science and Technology Fund (WWTF) and the City of Vienna through project LS18-111.
Duration: 01.03.2019 - 28.02.2022