TMOD-26. HUMAN GLIOBLASTOMA SLICE CULTURES AS A PLATFORM FOR IDENTIFICATION OF PATIENT-SPECIFIC DECREASE IN CELL MIGRATION AND RESPONSE TO THERAPY

摘要

Molecular heterogeneity in glioblastoma (GBM) is widely recognized at the inter-patient and intra-tumoral levels. More recently, we provided confirmation that endogenous heterogeneity also exists on a biological basis through analysis of migrating cells within ex vivo organotypic slice cultures from patients with primary GBM. These proof-of-principle studies demonstrated differential anti-invasive responses to gefitinib in slices from patients with or without EGFR amplification. Given these data, we concluded that greater insight into migrational heterogeneity may provide opportunities for personalized anti-invasive drug choices in GBM patients. To further explore this concept, we expanded upon the ex vivo slice culture paradigm to create a multi-drug testing platform that utilizes large-scale parallel analysis of slices from primary human GBM, through which we can visualize and screen across patients for effective reduction in cell migration in tightly controlled fashion. Using a panel of tyrosine kinase inhibitors chosen for their influence on migratory signaling pathways, preliminary data reveal differential responses from patient-to-patient across the drug spectrum. In some cases, up to a 30% reduction in migration speed were seen in response to specific drugs after short-term exposures. Critically, results from duplicate samples were consistent within tested individuals. These data suggest this model may be used to select patient-specific drug treatments based on modulation of a biologically important behavior and, while treatment variables such as drug concentration, length of treatment and combination strategies remain to be tested, we propose that this model may provide a preclinical stratification mechanism for identifying patient-specific anti-invasive therapies in GBM.