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.
胶质母细胞瘤是一种恶性脑肿瘤，因其侵袭性和浸润性特征而具有致命性。标准治疗方案包括手术切除、放疗以及使用替莫唑胺进行化疗，但对患者预后的改善作用有限（中位生存期仅为15个月）。因此，仍需通过临床前转化模型评估新型疗法，以提高患者的生存率和生活质量。在本项临床前研究中，我们评估了替莫唑胺在不同胶质母细胞瘤模型中的效果，并旨在探究芬戈莫德的疗效——该药物是一种用于治疗多发性硬化症的免疫调节剂，同时被描述为鞘氨醇-1-磷酸（S1P）/S1P受体轴抑制剂。我们通过体外二维和三维细胞实验，以及分别将小鼠和人类胶质母细胞瘤细胞植入免疫正常或免疫缺陷小鼠体内构建的体内模型，分析了芬戈莫德与替莫唑胺的作用。研究显示，在体外和体内模型中，替莫唑胺的效果因肿瘤类型（如U87MG、U118MG、U138MG和GL261）而异，呈现出敏感性、获得性耐药及完全耐药等肿瘤表型，这与临床观察一致。相比之下，芬戈莫德仅能在体外二维培养中抑制肿瘤细胞生长并增强细胞毒性。实际上，芬戈莫德对三维球状体的细胞毒性作用微弱甚至无效，且在替莫唑胺敏感模型中未表现出对体内肿瘤进展的抑制效果。这些结果表明芬戈莫德的疗效依赖于胶质母细胞瘤的肿瘤微环境。总体而言，我们的数据提示不同癌症模型对替莫唑胺的反应存在差异，这与其临床活性相符；而芬戈莫德的潜在活性可能值得进一步评估。
Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models
肿瘤(癌症)患者之家