Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

Abstract

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment.

Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma

“…The expression of p-ERK is reduced after exposure to MEK162 loaded polymersomes alone and when combined with TMZ. Actin is loading control 3D model systems in preclinical studies [20]. Currently, MEK inhibitors are in clinical trials, in particular for RAS or BRAF mutated tumours.…”

Radiotherapy and chemotherapy alter migration of brain cancer cells before cell death

“…Glioblastomas, the most aggressive primary brain tumors, are highly radio-resistant and chemoresistant, yet the standard of care in the clinic is still a triple modality of surgical resection followed by radiotherapy and chemotherapy [1,29]. In spite of this triple treatment modality, median survival of patients thus treated is still limited to 14 months, even with early detection and treatment [20,30]. Such abysmal outcome confirms the aggressive and invasive nature of GBM.…”

“…Instructively, 90% of GBMs relapse close (1-2 cm) to the primary tumor site following resection [31] . Both resection and targeted irradiation are believed to have limited success in eliminating tumors due to GBM diffusively invading surrounding tissues and evading and/or resisting treatment [20,32]. Even when concomitant and adjuvant chemotherapy are added to radiotherapy using drugs such as temozolomide (TMZ), local relapses occur and median survival remains 14 months compared to 12 months with RT alone [1].…”

“…Regarding measurement of migration, our method is not an end-point assessment as the Boyden chamber frequently used in previous reports, but a real time assay that measures both attachment and migration. Regarding setup and heterogeneity of glioma cells, the currently proposed need for personalized radiation medicine [4,20,21] informed our strategy, namely, an in vitro setup using that can be adopted for parallel monitoring of patient samples in the clinic so as to optimize treatments.…”

Profiling anti-apoptotic protein BCL-xL expression in U-87 MG glioblastoma cells and patient-derived tumorspheres

“…Similarly to neural stem cells which have the capacity to form neurospheres in vitro, GSCs have the ability to form clonogenic structures, called tumorspheres, in serum-free non-adherent conditions in vitro (6) (8). These 3D culture models therefore represent models of choice to unravel and test new therapeutic strategies to specifically target GSCs and prevent GBM development (9).…”