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Nat Commun. 2018 Nov 21;9(1):4904. doi: 10.1038/s41467-018-07334-3.

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

Author information

1
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
2
Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main St, Cambridge, MA, 02142, USA.
3
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
4
Department of Cancer Biology, Mayo Clinic, 13400 E. Shea Blvd.MCCRB 03-055, Scottsdale, AZ, 85259, USA.
5
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
6
Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, 55902, USA.
7
Department of Immunology, Mayo Clinic, 200 First St SW, Rochester, MN, 55902, USA.
8
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
9
Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, NY, 13902, USA.
10
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
11
Mathematical NeuroOncology Lab, Department of Neurosurgery, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.
12
Bruker Daltonics, Billerica, MA, 01821, USA.
13
Department of Chemistry and Chemical Biology, Northeastern University, 412 TF (140 The Fenway), Boston, MA, 02111, USA.
14
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Nathalie_Agar@dfci.harvard.edu.
15
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Nathalie_Agar@dfci.harvard.edu.
16
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA. Nathalie_Agar@dfci.harvard.edu.

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.

PMID:
30464169
PMCID:
PMC6249307
DOI:
10.1038/s41467-018-07334-3
[Indexed for MEDLINE]
Free PMC Article

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