An ex vivo functional biomarker of treatment response in pediatric low-grade glioma
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Background
Children with subtotally resected pediatric low-grade glioma (pLGG) often face multiple lines of treatment, which are seldom capable of eliminating the entire tumor. Genomics-based biomarkers are often used to select targeted therapies, but this paradigm only yields overall response rates of ∼50% optimally. Functional precision medicine (FPM), where patient-specific therapeutic efficacy is evaluated by directly treating individuals’ tumor outside their body, can predict individualized drug responses for some cancers, but pLGG is notoriously difficult to maintain outside the body, limiting development of FPM for pLGG.
Methods
We describe what is, to our knowledge, the first platform that can maintain, treat, and analyze zero-passage pLGG tumor tissue ex vivo , facilitating FPM testing. We engraft pLGG tumors onto a previously validated organotypic brain slice culture (OBSC) platform. After ensuring reproducible engraftment and maintenance of living pLGG tumor tissue on OBSCs, we measured MAPK pathway response to targeted therapies via immunoblotting. We then measured tumor ex vivo response to targeted therapies.
Results
Each zero-passage pLGG tumor tissue specimen exhibited reproducible growth on the OBSC platform. Western blot demonstrated each BRAF KIAA1549 fusion+ tumor exhibited expected paradoxical MAPK upregulation to dabrafenib treatment. Two of three tumors demonstrated cytotoxicity from trametinib as predicted, whereas one tumor did not. No clinical correlates were measured in this proof-of-concept study, though this mixed response to MEK inhibition may be in line with real-world clinical responses.
Conclusion
The OBSC platform supports ex vivo maintenance of passage-zero pLGG tumor tissue and enables personalized drug screening to yield a new functional biomarker of pLGG drug response.
