Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma.
Elizabeth C RandallKristina Bennet EmdalJanice K LaramyMinjee KimAlison RoosDavid CalligarisMichael S ReganShiv K GuptaAnn C MladekBrett L CarlsonAaron J JohnsonFa-Ke LuX Sunney XieBrian A JoughinRaven J ReddySen PengWalid M AbdelmoulaPamela R JacksonAarti KolluriKatherine A KellersbergerJeffrey N AgarDouglas A LauffenburgerKristin R SwansonNhan L TranWilliam F ElmquistForest M WhiteJann N SarkariaNathalie Y R AgarPublished in: Nature communications (2018)
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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- advanced non small cell lung cancer
- magnetic resonance
- mass spectrometry
- small cell lung cancer
- deep learning
- gene expression
- end stage renal disease
- newly diagnosed
- high resolution
- convolutional neural network
- adverse drug
- drug induced
- ejection fraction
- optical coherence tomography
- emergency department
- single cell
- prognostic factors
- computed tomography
- high density
- magnetic resonance imaging
- quality improvement
- machine learning
- heat shock protein
- gas chromatography
- small molecule
- amino acid
- smoking cessation
- optic nerve