Title | Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Randall EC, Emdal KB, Laramy JK, Kim M, Roos A, Calligaris D, Regan MS, Gupta SK, Mladek AC, Carlson BL, Johnson AJ, Lu F-K, X Xie S, 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 |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 4904 |
Date Published | 2018 11 21 |
ISSN | 2041-1723 |
Keywords | Animals, Antineoplastic Agents, ErbB Receptors, Erlotinib Hydrochloride, Female, Glioblastoma, Magnetic Resonance Imaging, Mice, Nude, Neoplasm Transplantation, Protein-Tyrosine Kinases, Sequence Analysis, RNA, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization |
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. |
DOI | 10.1038/s41467-018-07334-3 |
Alternate Journal | Nat Commun |
PubMed ID | 30464169 |
PubMed Central ID | PMC6249307 |
Grant List | K99 EB020749 / EB / NIBIB NIH HHS / United States P41 EB015898 / EB / NIBIB NIH HHS / United States R25 CA089017 / CA / NCI NIH HHS / United States U54 CA210180 / CA / NCI NIH HHS / United States |