gms | German Medical Science

72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

Targeting glioblastoma using a novel peptide specific to a deglycosylated isoform of brevican

Gezielte Glioblastomtherapie und -PET-Bildgebung mit einem neuen Peptid spezifisch für eine deglykosylierte Isoform von Brevican

Meeting Abstract

  • presenting/speaker Niklas von Spreckelsen - Universitätsklinikum Köln, Klinik für Neurochirurgie, Köln, Deutschland; BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten; Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten
  • Colin M. Fadzen - Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten
  • Nina Hartrampf - Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten; Universität Zürich, Chemie, Zürich, Schweiz
  • Yarah Ghotmi - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • Justin Wolfe - Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten
  • Shipra Dubey - BWH/Harvard Medical School, Radiology, Boston, MA, Vereinigte Staaten
  • Bo Yeun Yang - BWH/Harvard Medical School, Radiology, Boston, MA, Vereinigte Staaten
  • Marie Kijewski - BWH/Harvard Medical School, Radiology, Boston, MA, Vereinigte Staaten
  • Shuyan Wang - BWH/Harvard Medical School, Radiology, Boston, MA, Vereinigte Staaten
  • Charlotte Farquhar - Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten
  • Sonja Bergmann - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • Mykola Zdioruk - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • J. Roscoe Wasserburg - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • Emily Murrell - University of Western Ontario, Chemistry, London, Vereinigtes Königreich
  • Fernanda C. Bononi - University of Western Ontario, Chemistry, London, Vereinigtes Königreich
  • Leonard G. Luyt - University of Western Ontario, Chemistry, London, Vereinigtes Königreich
  • Marcelo Di Carli - BWH/Harvard Medical School, Radiology, Boston, MA, Vereinigte Staaten
  • Martine L. M. Lamfers - Erasmus MC, Neurosurgery, Rotterdam, Niederlande
  • Keith L. Ligon - Dana-Farber Cancer Institute/Harvard Medical School, Pathology, Boston, MA, Vereinigte Staaten
  • E. Antonio Chiocca - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • Mariano S. Viapiano - State University of New York UMU, Neuroscience and Physiology, Syracuse, NY, Vereinigte Staaten
  • Bradley L. Pentelute - Massachusetts Institute of Technology (MIT), Chemistry, Cambridge, MA, Vereinigte Staaten
  • Sean E. Lawler - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten
  • Choi-Fong Cho - BWH/Harvard Medical School, Neurosurgery, Boston, MA, Vereinigte Staaten

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocP125

doi: 10.3205/21dgnc413, urn:nbn:de:0183-21dgnc4131

Published: June 4, 2021

© 2021 von Spreckelsen et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Objective: Glioblastoma (GBM) is the most common and deadliest form of brain tumor and treatment options available today have limited success. Brevican (Bcan), a central nervous system (CNS)-specific extracellular matrix protein, is upregulated in high-grade glioma cells, including GBM. A Bcan isoform lacking most glycosylation, dg-Bcan, is found only in GBM tissues and therefore represents a viable target for tumor specific targeted therapy.Our objective was to explore dg-Bcan as a molecular target for GBM by identifying a dg-Bcan specific peptide.

Methods: A microfluidic chip for magnetic-activated sorting was used to screen a one bead one compound (OBOC) library containing a vast number of different D-peptides (theoretical diversity more than > 10^16 different unique peptides). Candidate peptides were then screened in vitro for affinity and specificity to dg-Bcan as well as cell uptake in patient derived GBM cells. The most promising candidate (BTP-7) was further evaluated in vivo, radiolabeled with 18F and used as a PET imaging agent in a GBM orthotopic xenograft mouse model. The potential of BTP-7 based targeted therapy was evaluated by functionalizing BTP-7 with camptothecin and testing its efficacy in vitro and in vivo.

Results: BTP-7 binds to dg-Bcan with high affinity and specificity (KD= 0.26 μM). BTP-7 is preferentially internalized by dg-Bcan-expressing patient derived glioma cells and can cross the blood-brain barrier (BBB) in vitro and in mice. Radiolabeled 18F-BTP-7 enabled PET imaging of orthotopic xenograft tumors in mice (n = 3/3). Conjugation of BTP-7 to camptothecin via a cleavable linker led to significantly increased DNA damage in intracranial GBM-6 tumors (p < 0.0001) and prolonged survival in tumor-bearing mice in comparison to vehicle and a scrambled control compound (Scr) (median survival in days = 73 (BTP-7) vs. 67 (Scr) vs. 46 (vehicle), p < 0.01 / p < 0.001); n = 7 mice per group).

Conclusion: dg-Bcan is an attractive molecular target for GBM, and BTP-7 represents a promising lead candidate for further development into novel imaging agents and targeted therapeutics.