Targeting the PI3K/Akt/mTOR Pathway in Glioblastoma Therapy

Glioblastoma is a highly aggressive primary brain tumour with limited treatment options. Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signalling cascade plays a central role in tumour cell survival, growth, migration and therapy resistance. Aberrant activation of this pathway arises from receptor tyrosine kinase alterations, loss of PTEN function and downstream feedback loops that enhance proliferation and inhibit apoptosis. Therapeutic strategies targeting PI3K, Akt and mTOR complexes aim to interrupt these pro-tumourigenic signals, overcome adaptive resistance and penetrate the central nervous system. Recent efforts focus on dual inhibitors that block multiple nodes within the cascade, combination regimens with standard chemoradiation or immunotherapy, and compounds engineered for efficient blood–brain barrier penetration. Emerging data suggest that a nuanced approach distinguishing between mTOR complex 1 (mTORC1) and complex 2 (mTORC2), addressing feedback activation of upstream kinases, and integrating novel delivery platforms may yield improved clinical benefit.

Research from Nature Portfolio

Studies on a novel pan-PI3K inhibitor have confirmed its ability to achieve sustained intracranial target engagement. This agent exhibits high oral bioavailability, negligible efflux at the blood–brain barrier and potent suppression of PI3K activity in preclinical models of glioblastoma. The combination of favourable pharmacokinetics and brain penetration positions this compound as a leading candidate for early-phase trials, with the potential to disrupt tumour growth by simultaneously inhibiting class I PI3K isoforms within the tumour microenvironment.

Targeting the PI3K/Akt/mTOR Pathway in Glioblastoma Therapy publication trend

The graph below shows the total number of articles in targeting the pi3k/akt/mtor pathway in glioblastoma therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Phosphoinositide 3-kinase (PI3K): A lipid kinase that phosphorylates phosphatidylinositols, initiating downstream Akt/mTOR signalling.

Akt (protein kinase B): A serine/threonine kinase activated by PI3K that promotes cell survival and growth.

mTOR (mechanistic target of rapamycin): A central kinase forming two complexes, mTORC1 and mTORC2, which regulate protein synthesis, metabolism and cytoskeletal dynamics.

mTORC1 and mTORC2: Distinct multiprotein assemblies of mTOR; mTORC1 primarily controls protein translation, while mTORC2 regulates cytoskeletal organisation and Akt activation.

Blood–brain barrier (BBB): A selective endothelium that limits passage of many therapeutic agents into the central nervous system.

Pan-PI3K inhibitor: A compound that targets multiple PI3K isoforms, enhancing the blockade of PI3K signalling in tumour cells.

Glioblastoma stem cells (GSCs): A subpopulation with self-renewal capacity that drives tumour recurrence and therapy resistance.

References

1. Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1. Cell Death Discovery (2024).
2. Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. International Journal of Molecular Sciences (2022).
3. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. International Journal of Molecular Sciences (2021).
4. Buparlisib is a brain penetrable pan-PI3K inhibitor. Scientific Reports (2018).