WEHI Wednesday Seminar hosted by Professor Grant Dewson

Ziyan Liu
PhD Student – Dewson Laboratory, Ubiquitin Signalling division, WEHI
(this is a PhD Completion seminar)

Towards better treatments for neuroblastoma

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Neuroblastoma is the most common extracranial solid tumour in infants and remains a leading cause of paediatric cancer death. Despite intensive treatment and significant treatment-related toxicity, nearly half of children with high-risk disease relapse with incurable disease. Hence, there is an urgent clinical need to develop safer and more effective treatment strategies.

During my PhD, I employed complementary approaches to identify new therapeutic vulnerabilities in high-risk neuroblastoma. First, I performed a genome-wide CRISPR interference screen to identify genes that could enhance the response of neuroblastoma cells to the BCL-2 inhibitor venetoclax, a targeted drug with a favourable safety profile but limited activity as a single agent. This screen identified regulators of the cell cycle as potential targets to sensitise neuroblastoma to venetoclax, which were validated across multiple preclinical models, including patient-derived xenograft (PDX) models.

As a targeted approach to complement the unbiased genetic screening, I pursued a hypothesis-driven investigation into the mitochondrial E3 ubiquitin ligase MARCHF5, exploring its role in neuroblastoma biology and its potential as a druggable target. I found that silencing MARCHF5 promotes sensitivity of neuroblastoma cells to BH3-mimetic drugs, including venetoclax, through a mechanism involving potentiation of BAX activation and oligomerisation.

Together, these findings aim to inform safer and more effective treatment strategies to improve outcomes for children with high-risk neuroblastoma.

All welcome!