WWTF LS18-111

WWTF LS18-111

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

Project Partners:
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

Project Abstract:

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.

Funding:
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
Link: https://www.wwtf.at/programmes/life_sciences/LS18-111/pdf/