Abstract A106: Pharmacological activation of CLIP3 reduces radioresistance by suppressing stemness and glycolysis in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of less than 15 months. GBM harbors glioblastoma stem cells (GSCs), which are crucial in therapeutic resistance and recurrence. Here, we report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain-containing linker protein 3 (CLIP3). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model. Collectively, our data suggest that repurposing glimepiride for GBM therapy could be an attractive strategy for overcoming tumor recurrence. [This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2020M2D9A2094156) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00207904).] Citation Format: Hyunkoo Kang, Eunguk Shin, Haksoo Lee, BuHyun Youn. Pharmacological activation of CLIP3 reduces radioresistance by suppressing stemness and glycolysis in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A106.