P14.23.B USE OF BIOPSY-DERIVED TUMOR ORGANOIDS FOR PERSONALIZED DRUG TESTING IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND To date, there are no systemic treatment options for patients suffering from recurrent glioblastoma with a proven efficacy. Furthermore, often surgical resection is not any more possible and patient tumors have acquired an increased chemo- and radioresistance. Patient-derived tumor organoids (TOs) provide a new exciting tool to test individual treatment responses. Aim of this study was to develop a protocol and to test the feasibility to perform personalized TO-based drug testing using the rare material from stereotactic biopsies. MATERIAL AND METHODS Patient-derived TOs were prepared based on single cell suspensions from tumor material obtained either from open glioblastoma resections serving as a reference data set (n=37) or from stereotactic biopsies of 8 patients. Drug response curves (6-9 dose points) were performed for nine selected drugs including temozolomide, lomustine, etoposide and temsirolimus, which are commonly used in clinical practice. Viability and metabolic activity were measured using CellTiterGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. Medical records were reviewed for survival and routine molecular information such as the MGMT promoter methylation status. RESULTS Drug testing performed on TOs derived from open resections allowed to adjust the concentration test range for each drug, as well as to determine the range of drug vulnerability. Additionally, we found a significant association between increased temozolomide sensitivity of TOs and both, MGMT methylation and increased survival. However, in 59% of the cases, no high sensitivity to any of the drugs was observed, and only 17% were highly sensitive to more than one drug. Subsequent drug testing on TOs derived from biopsies of recurrent glioblastoma revealed sensitivity in 3/8 cases against one (n=2) or two (n=1) of the drugs. However, sensitivity against drugs varied substantially in a patient-individual manner. CONCLUSION Taken together, we successfully developed a workflow to test drug sensitivity on glioblastoma-derived tumor organoids even from the low starting material obtained from stereotactic biopsies. Association of clinical outcome and MGMT methylation with temozolomide sensitivity corroborated the strength of this approach. Furthermore, patient-individual treatment responses strongly suggest for a future personalized drug testing.