Heterogeneous delivery across the blood-brain barrier limits the efficacy of an EGFR-targeting antibody drug conjugate in glioblastoma.

Autor:	Marin BM; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Porath KA; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Jain S; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Kim M; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Conage-Pough JE; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Oh JH; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Miller CL; Department of Bioengineering, Stanford University, Stanford, California, USA., Talele S; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Kitange GJ; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Tian S; Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Burgenske DM; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Mladek AC; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Gupta SK; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Decker PA; Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., McMinn MH; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA., Stopka SA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Regan MS; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., He L; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Carlson BL; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Bakken K; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Burns TC; Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA., Parney IF; Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA., Giannini C; Department of Laboratory Medicine and Pathology; Mayo Clinic, Rochester, Minnesota, USA., Agar NYR; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Eckel-Passow JE; Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Cochran JR; Department of Bioengineering, Stanford University, Stanford, California, USA., Elmquist WF; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Vaubel RA; Department of Laboratory Medicine and Pathology; Mayo Clinic, Rochester, Minnesota, USA., White FM; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA., Sarkaria JN; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2021 Dec 01; Vol. 23 (12), pp. 2042-2053.
DOI:	10.1093/neuonc/noab133
Abstrakt:	Background: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important. Methods: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics. Results: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment. Conclusions: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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