Advancing pineoblastoma treatment: A novel zebrafish disease model for preclinical therapeutic screening

Alexander Chan^{1, 2}, Oliva Palander¹, Liming Xu¹, Ian Bell¹, Laurie Liu^{1, 3}, Annie Huang^{1, 3}

¹Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children
²Department of Biomedical Engineering, University of Waterloo
³Department of Medical Biophysics, University of Toronto

ABSTRACT

Pineoblastoma (PB) is a rare and highly aggressive pediatric embryonal brain tumor (CNS WHO grade 4) characterized by a poor survival rate despite intensive cytotoxic chemotherapy and craniospinal radiotherapy. Because these intensive treatment strategies often cause severe side effects and lifelong cognitive complications in infants and young children, PB presents significant technical challenges for clinicians. The recent discovery of four molecular PB subgroups has further complicated our ability to determine optimal treatment and prognosis, as each subgroup responds differently to treatment. Among these subgroups, the PB-MYC subgroup is particularly aggressive, primarily occurring in children under three years of age with a five-year survival rate of only 20.5%.

Given the pressing need to define optimal treatment protocols for PB, we aim to use our novel zebrafish models to provide a rapid and low-cost in vivo platform for investigation. Benefiting from the optical accessibility of zebrafish embryos, our model enables real-time imaging of drug responses at both the cellular and mechanistic levels throughout key developmental events. This unique capability is pivotal for preclinical drug screening, enabling us to uncover the precise impact of potential treatments on tumorigenesis.

In this project, we demonstrate the success of our PB-MYC zebrafish model in recapitulating human physiology within this subgroup. We identified genes differentially expressed between zebrafish tumors and wild-type brain tissue and compared them with those in human PB tumors versus fetal brain tissue. Our correlation analyses revealed a significant similarity between the gene expression profiles in zebrafish tumors and human PB-MYC tumors. Thus, we anticipate our zebrafish model will provide critical insights into the molecular mechanisms driving PB, accelerating translational therapeutic efforts and ultimately improving survival and quality of life for young PB patients.