PIP4K2A-derived peptide PIP4-1 exhibits preferential antitumor activity in PTEN- deficient and patient-derived glioblastoma models

Abstract Glioblastoma (GBM) remains incurable despite surgery, radiotherapy and temozolomide (TMZ) chemotherapy, and molecular heterogeneity, therapy resistance and limited intracranial drug exposure sustain the need for pharmacologically distinct agents that are active in patient-relevant models. Because PIP4K2A restrains tumour progression in PTEN-deficient glioblastoma, we screened twelve cell-penetrating peptides derived from PIP4K2A in PDC1, a patient-derived culture in which PTEN and PIP4K2A protein were undetectable. PIP4-1 demonstrated the most reproducible concentration-dependent activity across two- and three-dimensional PDC1 cultures and retained activity in PDC4. In an exploratory murine comparison, PIP4-1 reduced viability to approximately 15% of control in PTEN-deficient GL26 cells but only to approximately 85% in PTEN-expressing GL261 cells (P = 4.69 × 10⁻⁵), identifying PTEN-low status as a candidate response context. At 200 µg/mL, PIP4-1 reduced viability more than 500 µM temozolomide in PDC1 and PDC4, although these models are not annotated for TMZ resistance. In a pilot subcutaneous xenograft study, PIP4-1 significantly reduced terminal tumour volume relative to vehicle. Keratinocyte and liver-organoid assays provided an initial tolerability context, suggesting a favorable safety profile. These data prioritize PIP4-1 as a lead candidate requiring mechanistic validation, selectivity assessment, stability and exposure studies, and efficacy testing in annotated orthotopic models.