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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\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      -mutated pHGG.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u00a0mg\/kg inavolisib and 100\u00a0mg\/kg ipatasertib). Finally, the in vivo efficacy of both inhibitors was evaluated using intracranial\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      -mutated pHGG xenograft models, with survival and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) levels as primary endpoints.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All 12 cell lines exhibited PI3K\/AKT alterations. The\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u20090.016 \u00b5M for inavolisib; 0.52 \u00b5M 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 \u00b5M and 0.93 \u00b5M, respectively. In vivo, inavolisib significantly extended survival (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0070) and increased CSF ctDNA release (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0317). In contrast, ipatasertib did not demonstrate significant in vivo activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings highlight the therapeutic potential of inavolisib for treating\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00280-026-04950-5","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T07:50:50Z","timestamp":1789631450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CNS distribution and preclinical activity of the PI3K\/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas"],"prefix":"10.1007","volume":"96","author":[{"given":"Leire","family":"Balaguer-Lluna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e0udia","family":"Resa-Par\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Brstilo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"G\u00f3mez-Caballero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Baulenas-Farr\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutian","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Aschero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaia","family":"Botteri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Li-Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Ma\u00f1ogil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Mart\u00ednez-Velasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Ruano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngela","family":"Garc\u00eda-Pelayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auriane","family":"Giron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Mora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Lavarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macarena","family":"S\u00e1nchez-Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meritxell","family":"Teixid\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Ormazabal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Artuch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Unceta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Schaiquevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8485-426X","authenticated-orcid":false,"given":"Angel M.","family":"Carcaboso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"issue":"8","key":"4950_CR1","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","volume":"23","author":"DN Louis","year":"2021","unstructured":"Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. 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