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 and Nathalie Y. R. Agar ()
Additional contact information
Elizabeth C. Randall: Harvard Medical School
Kristina B. Emdal: Massachusetts Institute of Technology
Janice K. Laramy: University of Minnesota
Minjee Kim: University of Minnesota
Alison Roos: Mayo Clinic
David Calligaris: Harvard Medical School
Michael S. Regan: Harvard Medical School
Shiv K. Gupta: Mayo Clinic
Ann C. Mladek: Mayo Clinic
Brett L. Carlson: Mayo Clinic
Aaron J. Johnson: Mayo Clinic
Fa-Ke Lu: Harvard Medical School
X. Sunney Xie: Harvard University
Brian A. Joughin: Massachusetts Institute of Technology
Raven J. Reddy: Massachusetts Institute of Technology
Sen Peng: Translational Genomics Research Institute
Walid M. Abdelmoula: Harvard Medical School
Pamela R. Jackson: Mayo Clinic
Aarti Kolluri: Mayo Clinic
Katherine A. Kellersberger: Bruker Daltonics
Jeffrey N. Agar: Northeastern University
Douglas A. Lauffenburger: Massachusetts Institute of Technology
Kristin R. Swanson: Mayo Clinic
Nhan L. Tran: Mayo Clinic
William F. Elmquist: University of Minnesota
Forest M. White: Massachusetts Institute of Technology
Jann N. Sarkaria: Mayo Clinic
Nathalie Y. R. Agar: Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07334-3

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