PI3K/AKT inhibitörleri inavolisib ve ipatasertib'in pediatrik tip diffüz yüksek dereceli gliomlardaki beyin omurilik sıvısı dağılımı ve preklinik aktivitesi

Özet (abstract)

Abstract Purpose Pediatric-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. Methods A 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. Results All 12 cell lines exhibited PI3K/AKT alterations. The PIK3CA H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC 50 = 0.016 µM for inavolisib; 0.52 µM for ipatasertib). PK modeling revealed geometric mean brain-to-plasma ratios of 0.07 for inavolisib and 0.20 for ipatasertib, with model-predicted maximum brain concentrations of 0.69 µM and 0.93 µM, respectively. In vivo, inavolisib significantly extended survival ( P = 0.0070) and increased CSF ctDNA release ( P = 0.0317). In contrast, ipatasertib did not demonstrate significant in vivo activity. Conclusion These 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.

Yazarların özeti; kaynağından alınmıştır. Cancer Chemotherapy and Pharmacology, 2026 · DOI ↗