2026-06-14T06:44:28Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/271512026-01-17T01:18:13Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616

00925njm 22002777a 4500 dc Castello-Pons, Maria author Ramírez-González, María A author Iglesias-Hernandez, Patricia author Lendo, Nermina Logo author Rodriguez-Martin, Carlos author Quiralte, Laura author Sepúlveda-Sánchez, Juan-Manuel author Dios Huerta, Olaya de author Gil, Carmen author Martínez, Ana author Sánchez-Gómez, Pilar author Casas-Tinto, Sergio author 2025-07 Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients. Castello-Pons M, Ramirez-Gonzalez MA, Iglesias-Hernández P, Lendo NL, Rodriguez-Martín C, Quiralte L, Sepúlveda-Sánchez JM, de Dios O, Gil C, Martínez A, Sánchez-Gómez P, Casas-Tinto S. VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context. Neurotherapeutics. 2025 Jul;22(4):e00576. doi: 10.1016/j.neurot.2025.e00576. Epub 2025 Mar 28. PMID: 40157890; PMCID: PMC12418426. 10.1016/j.neurot.2025.e00576 Neurotherapeutics 40157890 https://hdl.handle.net/20.500.12105/27151 GAL9 GSK-3β Macrophages PDE7A PTEN Tumor microenvironment VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context.