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Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma.
Salphati, Laurent; Alicke, Bruno; Heffron, Timothy P; Shahidi-Latham, Sheerin; Nishimura, Merry; Cao, Tim; Carano, Richard A; Cheong, Jonathan; Greve, Joan; Koeppen, Hartmut; Lau, Shari; Lee, Leslie B; Nannini-Pepe, Michelle; Pang, Jodie; Plise, Emile G; Quiason, Cristine; Rangell, Linda; Zhang, Xiaolin; Gould, Stephen E; Phillips, Heidi S; Olivero, Alan G.
Afiliação
  • Salphati L; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Alicke B; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Heffron TP; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Shahidi-Latham S; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Nishimura M; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Cao T; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Carano RA; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Cheong J; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Greve J; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Koeppen H; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Lau S; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Lee LB; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Nannini-Pepe M; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Pang J; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Plise EG; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Quiason C; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Rangell L; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Zhang X; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Gould SE; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Phillips HS; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
  • Olivero AG; Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S.-L., J.C., J.P., E.G.P., C.Q., X.Z.), Discovery Chemistry (T.P.H., A.G.O.), Cancer Signaling and Translational Oncology (B.A., M.N., M.N.-P., L.B.L., S.E.G., H.S.P.), Biomedical Imaging (T.C., R.A.C., J.G.), and Pathology (H.K., S.L., L.
Drug Metab Dispos ; 44(12): 1881-1889, 2016 12.
Article em En | MEDLINE | ID: mdl-27638506
ABSTRACT
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Limited treatment options have only marginally impacted patient survival over the past decades. The phophatidylinositol 3-kinase (PI3K) pathway, frequently altered in GBM, represents a potential target for the treatment of this glioma. 5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine (GDC-0084) is a PI3K inhibitor that was specifically optimized to cross the blood-brain barrier. The goals of our studies were to characterize the brain distribution, pharmacodynamic (PD) effect, and efficacy of GDC-0084 in orthotopic xenograft models of GBM. GDC-0084 was tested in vitro to assess its sensitivity to the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and in vivo in mice to evaluate its effects on the PI3K pathway in intact brain. Mice bearing U87 or GS2 intracranial tumors were treated with GDC-0084 to assess its brain distribution by matrix-assisted laser desorption ionization (MALDI) imaging and measure its PD effects and efficacy in GBM orthotopic models. Studies in transfected cells indicated that GDC-0084 was not a substrate of P-gp or BCRP. GDC-0084 markedly inhibited the PI3K pathway in mouse brain, causing up to 90% suppression of the pAkt signal. MALDI imaging showed GDC-0084 distributed evenly in brain and intracranial U87 and GS2 tumors. GDC-0084 achieved significant tumor growth inhibition of 70% and 40% against the U87 and GS2 orthotopic models, respectively. GDC-0084 distribution throughout the brain and intracranial tumors led to potent inhibition of the PI3K pathway. Its efficacy in orthotopic models of GBM suggests that it could be effective in the treatment of GBM. GDC-0084 is currently in phase I clinical trials.
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Base de dados: MEDLINE Assunto principal: Encéfalo / Neoplasias Encefálicas / Glioblastoma / Inibidores de Proteínas Quinases / Inibidores de Fosfoinositídeo-3 Quinase Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Buscar no Google
Imprimir
XML
PubMed Links

Base de dados: MEDLINE Assunto principal: Encéfalo / Neoplasias Encefálicas / Glioblastoma / Inibidores de Proteínas Quinases / Inibidores de Fosfoinositídeo-3 Quinase Idioma: En Ano de publicação: 2016 Tipo de documento: Article