Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Elizabeth C. Randall; Kristina B. Emdal; Janice K. Laramy; Minjee Kim; Alison Roos; David Calligaris; Michael S. Regan; Shiv K. Gupta; Ann C. Mladek; Brett L. Carlson; Aaron J. Johnson; Fa Ke Lu; X. Sunney Xie; Brian A. Joughin; Raven J. Reddy; Sen Peng; Walid M. Abdelmoula; Pamela R. Jackson; Aarti Kolluri; Katherine A. Kellersberger; Jeffrey N. Agar; Douglas A. Lauffenburger; Kristin R. Swanson; Nhan L. Tran; William F. Elmquist; Forest M. White; Jann N. Sarkaria; Nathalie Y.R. Agar

doi:10.1038/s41467-018-07334-3

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Elizabeth C. Randall, Kristina B. Emdal, Janice K. Laramy, Minjee Kim, Alison Roos, David Calligaris, Michael S. Regan, Shiv K. Gupta, Ann C. Mladek, Brett L. Carlson, Aaron J. Johnson, Fa Ke Lu, X. Sunney Xie, Brian A. Joughin, Raven J. Reddy, Sen Peng, Walid M. Abdelmoula, Pamela R. Jackson, Aarti Kolluri, Katherine A. KellersbergerJeffrey N. Agar, Douglas A. Lauffenburger, Kristin R. Swanson, Nhan L. Tran, William F. Elmquist, Forest M. White, Jann N. Sarkaria, Nathalie Y.R. Agar

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Abstract

Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.

Original language	English (US)
Article number	4904
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07334-3
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Randall, E. C., Emdal, K. B., Laramy, J. K., Kim, M., Roos, A., Calligaris, D., Regan, M. S., Gupta, S. K., Mladek, A. C., Carlson, B. L., Johnson, A. J., Lu, F. K., Xie, X. S., Joughin, B. A., Reddy, R. J., Peng, S., Abdelmoula, W. M., Jackson, P. R., Kolluri, A., ... Agar, N. Y. R. (2018). Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. Nature communications, 9(1), Article 4904. https://doi.org/10.1038/s41467-018-07334-3

Randall, EC, Emdal, KB, Laramy, JK, Kim, M, Roos, A, Calligaris, D, Regan, MS, Gupta, SK, Mladek, AC, Carlson, BL, Johnson, AJ, Lu, FK, Xie, XS, Joughin, BA, Reddy, RJ, Peng, S, Abdelmoula, WM, Jackson, PR, Kolluri, A, Kellersberger, KA, Agar, JN, Lauffenburger, DA, Swanson, KR , Tran, NL, Elmquist, WF, White, FM, Sarkaria, JN & Agar, NYR 2018, 'Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma', Nature communications, vol. 9, no. 1, 4904. https://doi.org/10.1038/s41467-018-07334-3

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abstract = "Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling.",

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AU - Kellersberger, Katherine A.

AU - Agar, Jeffrey N.

AU - Lauffenburger, Douglas A.

AU - Swanson, Kristin R.

AU - Tran, Nhan L.

AU - Elmquist, William F.

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AU - Sarkaria, Jann N.

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Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

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