NEW YORK – An international team led by investigators in Australia has established a multiomics-informed cell line atlas for hundreds of pediatric cancer cell lines, pointing to potential driver mechanisms, treatment targets, and response biomarkers.
"We now know that pediatric cancers are different from adult cancers, even when they occur in the same tissue," senior and corresponding author Ron Firestein, a researcher with Monash University's Centre for Cancer Research and its molecular and translational science department, said in an email. "This highlights a need to develop new tools and resources for childhood cancers."
For a paper published in the journal Cancer Cell on Thursday, he and his colleagues used a combination of whole-genome sequencing, RNA sequencing, array-based methylation profiling, CRISPR-based essential gene analyses, small molecule screening, and/or other functional analyses to profile 261 tumor cell lines, including 182 cell lines profiled with multiomic, functional genomic, and drug testing approaches.
The cell line set represented 18 pediatric brain cancer, sarcoma, and other cancer types, along with 31 adult glioma cell lines, patient-derived fibroblast lines, and cell lines generated from normal brain or bone samples.
"By sequencing these tumor models across multiple dimensions, we've been able to improve the subclassification of pediatric cancer models and match them to clinically defined subtypes," Firestein said. "Importantly, by then integrating the molecular features of these models with drug and genetic (CRISPR) screens, we are able to identify distinct therapeutic vulnerabilities that can be matched to biomarkers that predict their response."
The resulting Childhood Cancer Model Atlas (CCMA) "provides a comprehensive single-site resource of hundreds of pediatric cancer cell lines," he explained.
Using the integrated dataset generated for the atlas, the investigators turned to machine learning approaches and predictive modeling to pin down potential treatment targets and related biomarker candidates.
Along with recurrent alterations affecting established oncogenes and tumor suppressor genes, the team's analyses revealed distinct features found in the pediatric cancer cells, including an overrepresentation of candidate cancer drivers in pathways involved in epigenetic regulation, anti-apoptosis mechanisms, and receptor tyrosine kinase activity.
In atypical teratoid rhabdoid tumors, for example, the investigators tracked down potentially targetable mutations in the chromatin-related gene KMT2A, while HDAC2 alterations turned up in diffuse midline glioma containing histone H3.3-K27M alterations, suggesting this tumor subset may respond to HDAC2 inhibitors.
"Our finding that adult cancer biomarkers of therapeutic response are not typically predictive in pediatric cancers underscores the importance of large-scale pediatric cancer efforts such as CCMA for advancing pediatric cancer targeted therapies," the authors explained. "As such, our work advocates for a pediatric-centric approach that will aid in developing precision medicine approaches and informing pediatric cancer clinical trial design."
The team's analyses also highlighted treatment response-related mutations in the PDGFRA, along with other potential biomarker genes showing genetic variation or expression patterns that tracked with responses to one or more of the treatments considered.
"Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance," the study's authors wrote.
Data from the CCMA are available through an online data portal, Firestein said, noting that the site includes artificial intelligence features and "provides information on both the models and enables analytical queries into our complete dataset."
"[W]e envision this resource being utilized by researchers and clinicians to generate and validate hypotheses regarding biological pathways and therapeutic vulnerabilities in different types of pediatric cancers," he said.