title: Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma.
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.
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California salphati.laurent@gene.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Sheerin
authors.initials: S
authors.lastname: Shahidi-Latham
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Merry
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Tim
authors.initials: T
authors.lastname: Cao
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Carano
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Joan
authors.initials: J
authors.lastname: Greve
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Shari
authors.initials: S
authors.lastname: Lau
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini-Pepe
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Cristine
authors.initials: C
authors.lastname: Quiason
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Linda
authors.initials: L
authors.lastname: Rangell
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.affiliation: 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.R.), Genentech Inc., South San Francisco, California.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000378:metabolism / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors