Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review
"Paxalisib, a dual PI3K/mTOR inhibitor specifically developed for the treatment of GBM, has demonstrated favourable safety profile and promising efficacy as a first-line treatment in a Phase 2 trial, and is being further investigated in patients with newly diagnosed or recurrent GBM as a part of the AGILE GBM trial [102, 103]. However, recent preclinical studies have revealed that tumour cells in GBM and other cancers may circumvent PI3K inhibition by inducing insulin feedback as a resistance mechanism to reactivate PI3K-mTOR signalling, suggesting that PI3K inhibitors may need to be coupled with anti-hyperglycemic therapies such as metformin to increase treatment efficacy [104, 105]. Correspondingly, a clinical trial is therefore underway to assess the clinical value of this strategy by combining paxalisib with metformin and a ketogenic diet (NCT05183204"
