Modl-03. an ex vivo platform based on organotypic brain slice culture for informing personalized brain cancer therapy

Abstract While the improved classification of CNS tumors is already enhancing the scientific rigor of clinical brain cancer treatment guidelines, the impact of these integrated diagnoses based on histopathological features or molecular insight on precision oncology medicine has yet to demonstrate widespread clinical benefit. Patient tumor-derived cancer models, including patient tumor-derived cell lines, organoids, and explants, have provided practical models based on a patient’s individual tumor for effective therapeutic drugs. Importantly, patient tumor-derived organoids have shown potential to guide personalized care and optimize clinical outcomes by functionally predicting patient response to antitumor drugs prior to in vivo treatment. Our team has built an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm that allows for the ex vivo engraftment, rapid treatment, and systemic analysis of resected patient brain tumor tissue. This OBSC platform has successfully supported engraftment of each patient tumor tested to this point, including high- and low-grade adult and pediatric tumor tissue. The established patient tumor-derived organoids show the ability to activate the endogenous astrocytes within OBSCs, which have been reported in brain tumor. Whole exome sequencing analysis showed that patient tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to their parent tumor, while tumor tissue expanded in vitro displayed a distinctly different DNA profile. Additionally, our algorithm calculates dose-response relationships of both tumor kill and normal brain tissue toxicity, generating summarized drug sensitivity scores based on therapeutic window and allowing us to normalize response profiles across a panel of FDA-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment revealed positive associations to clinical outcomes, suggesting the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.