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Research ArticleArticle

Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma

Laurent Salphati, Bruno Alicke, Timothy P. Heffron, Sheerin Shahidi-Latham, Merry Nishimura, Tim Cao, Richard A. Carano, Jonathan Cheong, Joan Greve, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Michelle Nannini-Pepe, Jodie Pang, Emile G. Plise, Cristine Quiason, Linda Rangell, Xiaolin Zhang, Stephen E. Gould, Heidi S. Phillips and Alan G. Olivero
Drug Metabolism and Disposition December 2016, 44 (12) 1881-1889; DOI: https://doi.org/10.1124/dmd.116.071423
Laurent Salphati
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
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Bruno Alicke
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
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Timothy P. Heffron
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
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Sheerin Shahidi-Latham
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
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Merry Nishimura
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
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Tim Cao
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
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Richard A. Carano
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
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Jonathan Cheong
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
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Joan Greve
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
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Hartmut Koeppen
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
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Shari Lau
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
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Leslie B. Lee
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
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Michelle Nannini-Pepe
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
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Jodie Pang
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
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Emile G. Plise
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
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Cristine Quiason
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
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Linda Rangell
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
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Xiaolin Zhang
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
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Stephen E. Gould
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
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Heidi S. Phillips
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
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Alan G. Olivero
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
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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.

Footnotes

    • Received May 6, 2016.
    • Accepted September 9, 2016.
  • dx.doi.org/10.1124/dmd.116.071423.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Research ArticleArticle

GDC-0084 Brain Penetrant PI3K Inhibitor against GBM

Laurent Salphati, Bruno Alicke, Timothy P. Heffron, Sheerin Shahidi-Latham, Merry Nishimura, Tim Cao, Richard A. Carano, Jonathan Cheong, Joan Greve, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Michelle Nannini-Pepe, Jodie Pang, Emile G. Plise, Cristine Quiason, Linda Rangell, Xiaolin Zhang, Stephen E. Gould, Heidi S. Phillips and Alan G. Olivero
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1881-1889; DOI: https://doi.org/10.1124/dmd.116.071423

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Research ArticleArticle

GDC-0084 Brain Penetrant PI3K Inhibitor against GBM

Laurent Salphati, Bruno Alicke, Timothy P. Heffron, Sheerin Shahidi-Latham, Merry Nishimura, Tim Cao, Richard A. Carano, Jonathan Cheong, Joan Greve, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Michelle Nannini-Pepe, Jodie Pang, Emile G. Plise, Cristine Quiason, Linda Rangell, Xiaolin Zhang, Stephen E. Gould, Heidi S. Phillips and Alan G. Olivero
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1881-1889; DOI: https://doi.org/10.1124/dmd.116.071423
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