The Feasibility of Combining Brain Radiation and Fingolimod in Healthy Rodents and in Humans With Newly Diagnosed Glioblastoma

Grossman, Stuart A.; Piotrowski, Anna F.; Jackson, Dvone; Nirschl, Thomas R.; Velarde, Esteban; Wong, John; Drake, Charles G.; Ye, Xiaobu

doi:10.21203/rs.3.rs-251903/v1

Cited by 2 publications

(3 citation statements)

References 22 publications

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“…Fingolimod and Fingolimod phosphate have a low renal clearance associated with a drug half-life of around 6–9 days and thus display stable concentrations in the bloodstream [ 81 ]. Nevertheless, only one not-yet-peer-reviewed clinical study has been carried out in the GBM context, but no data on efficacy were evaluated [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Davy,

Genest,

Legrand

et al. 2023

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Davy,

Genest,

Legrand

et al. 2023

Cancers

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“…The most frequent drug used in this context is FTY720 (fingolimod) from Novartis that was initially used as a drug for the treatment of multiple sclerosis. Grossman et al examined the feasibility of combining Fingolimod to the standard-of-care for newly diagnosed GBM patients in a single arm trial [ 170 ]. The results of this trial highlighted important safety concerns with this combination, including prolonged lymphopenia [ 170 ].…”

Section: Clinical Trials Using Activators or Inhibitors Of Pp2amentioning

confidence: 99%

“…Grossman et al examined the feasibility of combining Fingolimod to the standard-of-care for newly diagnosed GBM patients in a single arm trial [ 170 ]. The results of this trial highlighted important safety concerns with this combination, including prolonged lymphopenia [ 170 ]. It is reported that FTY720 can indirectly activate PP2A by blocking SET binding [ 171 ].…”

Section: Clinical Trials Using Activators or Inhibitors Of Pp2amentioning

confidence: 99%

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

Kashani

Vassella

2022

Cancers

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Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on “glioblastoma, IDH wild-type” (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.

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The Feasibility of Combining Brain Radiation and Fingolimod in Healthy Rodents and in Humans With Newly Diagnosed Glioblastoma

Cited by 2 publications

References 22 publications

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

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