The Comparative Oncology Trials Consortium at the National Cancer Institute have been performing canine glioma pre-clinical trials to evaluate therapeutic strategies for human and canine benefit. However, the similarity between human and canine glioma at the molecular and genomic level is unknown. We recently addressed this knowledge gap by reporting on the genomic landscape of canine glioma, to demonstrate that this is similar to the genomic landscape of human glioma, and pediatric high-grade glioma in particular. We found that aneuploidy was a major driver of canine and pediatric glioma. Aneuploidy is a predominant cancer feature but the functional consequences of aneuploidy are not well understood. Identification and functional characterization of aneuploidy events has a potential clinical merit as they impact prognosis and response to immunotherapy8. We hypothesize that conserved synteny between canine and human genome contain potential oncogenes and tumor-suppressor genes that cancer cells adapt to by accumulating aneuploid gains and losses. We propose to leverage our large genomic datasets of canine and human glioma to identify potential gene targets located in syntenic aneuploidy regions. We will then use high-throughput functional screens of canine and human glioma model systems, to prioritize genes as potential drug targets for glioma therapy.
This cross-species comparison study will define significant gene targets functionally and accelerate human glioma therapeutics development by providing rationales for canine glioma preclinical trials and human clinical trials.
What are the goals of this project?
The goals of this project are to evaluate genes as functional tumor suppressor genes and as potential oncogenes using CRISPR gene knockout approaches in both canine and pediatric glioma cell lines.
What is the impact of this project?
We expect that we will see convergence of the most impactful molecular abnormalities on mechanisms, which will implicate that these mechanisms are candidates for the development of new drugs. Our project will provide a basis for the development of new therapies and repurposing of existing drugs for kids and dogs with brain cancer.
Why the CBTN request is important to this project?
CBTN provided pediatric high-grade glioma data resources and cell lines will be crucial for both of our aims. Specifically, available cell-line and patient WGS and RNA-seq data will be used to identify aneuploidy in conserved synteny regions. Cell-lines will then be subject to low pass WGS to screen for candidate aneuploidy shared with canine glioma derived cell lines. Two of candidate aneuploid cell lines will further be used for CRISPR-Cas9 assay and in-vitro assays to validate effect of gene knock-out.
The Children's Brain Tumor Network will contribute to this project by providing cell lines.
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective