Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Simple Summary Grade 4 gliomas and glioblastomas are the most common brain tumors, accounting for 50% of primary brain tumors, and the most aggressive, with a median 5-year patient survival of less than 10%. There is no therapy to date that can sustainably prolong the life of patients. In this work, we demonstrated that the standard of care, Temozolomide, and Fingolimod, an immunomodulatory molecule with expected anti-cancer activity, reduced tumor cell survival in vitro. Conversely, Temozolomide reduced tumor growth in vivo in mouse and human orthotopic glioblastoma models, while Fingolimod did not. Globally, our data suggest that the Temozolomide response varies depending on the type of cancer model and that the efficacy of Fingolimod may still need confirmation.Abstract Glioblastomas are malignant brain tumors which remain lethal due to their aggressive and invasive nature. The standard treatment combines surgical resection, radiotherapy, and chemotherapy using Temozolomide, albeit with a minor impact on patient prognosis (15 months median survival). New therapies evaluated in preclinical translational models are therefore still required to improve patient survival and quality of life. In this preclinical study, we evaluated the effect of Temozolomide in different models of glioblastoma. We also aimed to investigate the efficacy of Fingolimod, an immunomodulatory drug for multiple sclerosis also described as an inhibitor of the sphingosine-1-phosphate (S1P)/S1P receptor axis. The effects of Fingolimod and Temozolomide were analyzed with in vitro 2D and 3D cellular assay and in vivo models using mouse and human glioblastoma cells implanted in immunocompetent or immunodeficient mice, respectively. We demonstrated both in in vitro and in vivo models that Temozolomide has a varied effect depending on the tumor type (i.e., U87MG, U118MG, U138MG, and GL261), demonstrating sensitivity, acquired resistance, and purely resistant tumor phenotypes, as observed in patients. Conversely, Fingolimod only reduced in vitro 2D tumor cell growth and increased cytotoxicity. Indeed, Fingolimod had little or no effect on 3D spheroid cytotoxicity and was devoid of effect on in vivo tumor progression in Temozolomide-sensitive models. These results suggest that the efficacy of Fingolimod is dependent on the glioblastoma tumor microenvironment. Globally, our data suggest that the response to Temozolomide varies depending on the cancer model, consistent with its clinical activity, whereas the potential activity of Fingolimod may merit further evaluation.

Automated summary

Grade 4 gliomas and glioblastomas are the most common and aggressive brain tumors. Temozolomide, the current standard treatment, has varying responses depending on the tumor type, while Fingolimod, an immunomodulatory drug, may need further evaluation for its potential activity. The study highlights the need for new therapies to improve survival and quality of life for glioblastoma patients.