ArticleCancer chemotherapy and pharmacology2026
CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas.
Article in Cancer chemotherapy and pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
purposePediatric-type diffuse high-grade gliomas (pHGG) are aggressive, largely incurable malignancies often characterized by PI3K/AKT pathway activation. This study investigated whether the PI3K inhibitor inavolisib and the AKT inhibitor ipatasertib could achieve therapeutic concentrations in the central nervous system (CNS) and demonstrate efficacy against PIK3CA-mutated pHGG.
methodsA panel of 12 pHGG cell lines with diverse PI3K/AKT genetic aberrations was screened for sensitivity to inavolisib and ipatasertib. Pharmacokinetic (PK) modeling was performed in mice to determine brain-to-plasma exposure ratios following oral administration (50 mg/kg inavolisib and 100 mg/kg ipatasertib). Finally, the in vivo efficacy of both inhibitors was evaluated using intracranial PIK3CA-mutated pHGG xenograft models, with survival and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) levels as primary endpoints.
resultsAll 12 cell lines exhibited PI3K/AKT alterations. The PIK3CA H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC
conclusionThese findings highlight the therapeutic potential of inavolisib for treating PIK3CA-mutated pHGG. Despite the blood-brain barrier, inavolisib achieved sufficient CNS exposure to prolong survival in preclinical models, whereas ipatasertib efficacy did not translate from in vitro to in vivo settings.
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