Poster Presentation 38th Lorne Cancer Conference 2026

Investigating initiating factors in neuroblastoma development from prevention to therapy (#108)

Domenico Abruzzese 1 2 , Jayne Murray 1 2 , Quenten Schwarz 3 , Dione Gardner-Stephen 3 , Ceilidh Marchant 3 , Jamie I Fletcher 1 2 , Frances L Byrne 4 , Ellen Olzomer 4 , Orazio Vittorio 5 , Murray D Norris 1 2 , Jessica L Bell 2 6
  1. Experimental Therapeutics & Molecular Oncology, Children’s Cancer Institute, Sydney, NSW , Australia
  2. School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  3. Neurovascular Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
  4. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia
  5. School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  6. Brain Tumour Group, Children’s Cancer Institute, Sydney, NSW, Australia

Neuroblastoma is the most common extracranial solid tumour of childhood and remains lethal for up to a third of children. Embryonic factors, both environmental and genetic, presumably work in concert to contribute to its development, yet these remain poorly understood. This project investigates two novel genes in neuroblastoma development: UBIAD1 and RUNX1T1. Almost half of all high-risk neuroblastomas are MYCN driven, 70% of these harbouring a 1p chromosomal LOH. Despite 1p harbouring the UBIAD1 gene, which is a tumour suppressor in other cancers (notably lymphoma and bladder cancer), this Vitamin K2 (K2) synthesis enzyme is yet to be studied in neuroblastoma. We found that UBIAD1 mRNA levels are decreased in 1p deleted tumours, and that low DNA/ mRNA levels of UBIAD1 were associated with decreased patient survival, presenting the possibility that low UBIAD1 expression might be rescued by K2 supplementation. Interestingly, treating both MYCN and MYC expressing neuroblastoma cell lines with K2 caused decreased MYCN/MYC and BCL-2 protein expression, as well as induction of apoptosis. No cytotoxic effects were seen in non-malignant cells up to the highest dose of 80µM. K2 treatment also induces oxidative stress and lactate accumulation. Because K2 is easily supplemented, ongoing studies will assess the efficacy of supplementation on MYCN-driven mouse models of neuroblastoma. RUNX1T expression was recently reported by our group to be essential for MYCN-driven neuroblastoma development (Nature Communications, 2024), with a single point mutation completely preventing neuroblastoma in mice. To test whether RUNX1T1 is required for MYCN-driven neuroblastoma initiation in a human pre-clinical model, we established a human iPSC neuroblastoma platform by CRISPR-Cas9/Prime editing to generate isogenic RUNX1T1 mutant lines. Ongoing research will utilise scRNA-seq trajectories and chart RUNX1T1 controlled networks, derive a dependency signature, and compute compounds that phenocopy early RUNX1T1 depletion via Connectivity Map (CMAP) analytics. With the current research emphasis on precision medicine based on rare somatic mutations, my work instead makes major inroads into understanding the cause of neuroblastoma and development of treatments based on underlying changes that support MYCN oncogenesis to help drive these approaches.