Patient-Derived Tumor Organoids for Guidance of Personalized Drug Therapies in Recurrent Glioblastoma

Abstract

An obstacle to effective uniform treatment of glioblastoma, especially at recurrence, is genetic and cellular intertumoral heterogeneity. Hence, personalized strategies are necessary, as are means to stratify potential targeted therapies in a clinically relevant timeframe. Functional profiling of drug candidates against patient-derived glioblastoma organoids (PD-GBO) holds promise as an empirical method to preclinically discover potentially effective treatments of individual tumors. Here, we describe our establishment of a PD-GBO-based functional profiling platform and the results of its application to four patient tumors. We show that our PD-GBO model system preserves key features of individual patient glioblastomas in vivo. As proof of concept, we tested a panel of 41 FDA-approved drugs and were able to identify potential treatment options for three out of four patients; the turnaround from tumor resection to discovery of treatment option was 13, 14, and 15 days, respectively. These results demonstrate that this approach is a complement and, potentially, an alternative to current molecular profiling efforts in the pursuit of effective personalized treatment discovery in a clinically relevant time period. Furthermore, these results warrant the use of PD-GBO platforms for preclinical identification of new drugs against defined morphological glioblastoma features.

Development of In Vitro Assays for Advancing Radioimmunotherapy against Brain Tumors

“…Testing has revealed the 50% effective dose (EC50) at 7.64 ng durvalumab/mL (0.0522 nM) [ 41 ] and the manufacturer quotes a half-maximal inhibitory concentration (IC50) of 0.1 nM, approximately double the EC50 dose. Based on the recommendations of Liston and Davis [ 38 , 42 ], in testing, concentrations were kept below 10 times the IC50 to avoid effects outside of clinically relevant doses. Preparation of the doses of durvalumab mirrored that of the temozolomide; however, per recommendations from the manufacturer, stock solutions were not stored for extended periods and the undiluted solution was kept at 2–4 °C to avoid antibody deactivation.…”

Glioblastoma Microenvironment and Invasiveness: New Insights and Therapeutic Targets

“…To understand comprehensively the interaction of cellular heterogeneity and pathways involved in glioblastoma invasiveness requires the use of clinically relevant models that embrace the complexity and the biology of parent tumors. Patient-derived glioblastoma organoids (PD-GBOs) have emerged as a more accurate and potentially feasible field in the study of this biology and as a preclinical ex vivo model [ 181 ]. PD-GBO models, unlike traditional in vitro models such as monolayer tumor sphere cultures (neurospheres), are able to maintain intra-tumoral heterogeneity and expression of key parental tumor genes [ 182 , 183 , 184 ].…”

“…To address this limitation, PD-GBOs can be co-cultured [ 184 ] or bioprinted on a chip [ 191 ] with multiple cell types or grown as an air–liquid interface protocol [ 192 ] that is able to maintain the microenvironment for almost 60 days. All this background information shows that the PD-GBCs platform has potential in the study of microenvironment interactions, invasiveness for preclinical identification of new drugs, and immunotherapy [ 181 ].…”

Development of glioblastoma organoids and their applications in personalized therapy

“…Moreover, brain organoids induced by GBM pathology, particularly organoids generated by patient-derived cells, have been used to test the therapeutic efficacy of various treatments, such as radiotherapy 22 and chemotherapy 93 . Organoid models can be exploited for functional analysis of anticancer drugs 94 for preclinical screening and identification targeting specific glioma subtypes, thus providing an effective platform for drug discovery 95 . Future research will focus on developing protocols to rapidly generate patient-specific organoids so that they can be used to test the efficacy of existing clinical treatments, thereby providing a basis for patient-specific drug selection.…”