VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context.

in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics by Maria Castello-Pons, Maria A Ramirez-Gonzalez, Patricia Iglesias-Hernández, Nermina Logo Lendo, Carlos Rodriguez-Martín, Laura Quiralte, Juan-Manuel Sepúlveda-Sánchez, Olaya de Dios, Carmen Gil, Ana Martínez, Pilar Sánchez-Gómez, Sergio Casas-Tinto

TLDR

  • VP3.15, a dual inhibitor of GSK-3β and PDE7, demonstrated anti-tumor efficacy against glioblastoma cells and reduced systemic inflammation in a Drosophila melanogaster glioma model.
  • The study suggests that VP3.15 could be a potential treatment option for glioblastoma patients with wild-type PTEN, but further clinical trials are needed to confirm its efficacy.
  • The study highlights the importance of considering PTEN genetic status when selecting treatments for glioblastoma.

Abstract

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.

Overview

  • The study assessed the therapeutic potential of VP3.15, a dual inhibitor of GSK-3β and PDE7, in a Drosophila melanogaster glioma model.
  • VP3.15 showed anti-tumor efficacy against human and mouse GB cells, but its capacity to inhibit orthotopic growth was dependent on the PTEN genetic status.
  • The study aimed to identify effective treatments for glioblastoma, a brain cancer with no cure, by either discovering new molecules or repurposing existing ones.

Comparative Analysis & Findings

  • VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells.
  • The capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line.
  • The analysis of VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization.

Implications and Future Directions

  • The study suggests that VP3.15 could be a safe and effective treatment option for glioblastoma patients with wild-type PTEN.
  • Future studies should investigate the potential of VP3.15 in clinical trials for glioblastoma patients.
  • The study's findings also highlight the importance of considering PTEN genetic status when selecting treatments for glioblastoma.
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