Buonaiuto Michela, Cuomo Mariella, Costabile Davide, Trio Federica, Ferraro Sara, Affinito Ornella, De Bellis Alberto, Del Basso De Caro Maria Laura, Visconti Roberta, Chiariotti Lorenzo, Catapano Giuseppe, Della Monica Rosa
CEINGE-Advanced Biotechnologies "Franco Salvatore", Naples, Italy.
Department of Molecular Medicine and Medical Biotechnologies, University of Napoli "Federico II", Naples, Italy.
J Transl Med. 2025 Jul 10;23(1):779. doi: 10.1186/s12967-025-06767-x.
Glioblastoma is the most aggressive type of brain tumor and is associated with a poor prognosis. First-line treatment is surgical resection followed by radiotherapy and temozolomide-based chemotherapy. However, the duration of treatment with temozolomide is limited due to both its toxicity and the development of drug resistance. The prognostic and predictive factor for response to temozolomide is the methylation status of the MGMT promoter. Indeed, loss of MGMT promoter methylation is a major cause of chemoresistance. However, the development of drug resistance is not only associated with changes in MGMT methylation. The entire epigenome changes and acquires specific properties necessary for tumor progression.
To study epigenetic alterations associated with temozolomide exposure, we generated a TMZ-resistant cell model. We investigated epigenetic alterations in the cell model and in a cohort of patients with recurrent glioblastoma using genome-wide methylome approaches (Epic Arrays 850 k).
We investigated the epigenetic changes associated with temozolomide exposure. Therefore, we generated a TMZ-resistant cell model and studied the epigenetic features acquired after selective temozolomide pressure. Our next step was to investigate the epigenomic differences between primary and recurrent tumors in a small cohort of patients. Finally, we performed a cross-analysis between the epigenetic differences found in TMZ-resistant cells and recurrent glioblastomas to identify common signatures that could be used to guide future resistance-overcoming studies.
Temozolomide induces significant epigenetic changes in glioblastoma, which may contribute to treatment resistance and increased tumor aggressiveness. The results suggest that further research into DNA methylation changes associated with TMZ resistance is crucial. The use of primary tumor cells in resistance models may help identify strategies to overcome chemoresistance in glioblastoma.
胶质母细胞瘤是最具侵袭性的脑肿瘤类型，预后较差。一线治疗是手术切除，随后进行放疗和基于替莫唑胺的化疗。然而，由于替莫唑胺的毒性和耐药性的产生，其治疗持续时间有限。替莫唑胺反应的预后和预测因素是MGMT启动子的甲基化状态。事实上，MGMT启动子甲基化缺失是化疗耐药的主要原因。然而，耐药性的产生不仅与MGMT甲基化的变化有关。整个表观基因组发生变化并获得肿瘤进展所需的特定特性。
为了研究与替莫唑胺暴露相关的表观遗传改变，我们构建了一个对替莫唑胺耐药的细胞模型。我们使用全基因组甲基化组方法（Epic Arrays 850k）研究了细胞模型和复发性胶质母细胞瘤患者队列中的表观遗传改变。
我们研究了与替莫唑胺暴露相关的表观遗传变化。因此，我们构建了一个对替莫唑胺耐药的细胞模型，并研究了在选择性替莫唑胺压力后获得的表观遗传特征。我们的下一步是在一小群患者中研究原发性肿瘤和复发性肿瘤之间的表观基因组差异。最后，我们对在替莫唑胺耐药细胞和复发性胶质母细胞瘤中发现的表观遗传差异进行了交叉分析，以确定可用于指导未来克服耐药性研究的共同特征。
替莫唑胺在胶质母细胞瘤中诱导显著的表观遗传变化，这可能导致治疗耐药性和肿瘤侵袭性增加。结果表明，进一步研究与替莫唑胺耐药相关的DNA甲基化变化至关重要。在耐药模型中使用原发性肿瘤细胞可能有助于确定克服胶质母细胞瘤化疗耐药性的策略。
