Bianca-Maria Marin1, Kendra A Porath1, Sonia Jain1, Minjee Kim2, Jason E Conage-Pough3,4,5, Ju-Hee Oh2, Caitlyn L Miller6, Surabhi Talele2, Gaspar J Kitange1, Shulan Tian7, Danielle M Burgenske1, Ann C Mladek1, Shiv K Gupta1, Paul A Decker7, Madison H McMinn8,9, Sylwia A Stopka8,10, Michael S Regan8, Lihong He1, Brett L Carlson1, Katrina Bakken1, Terence C Burns11, Ian F Parney11, Caterina Giannini12, Nathalie Y R Agar8,10,13, Jeanette E Eckel-Passow7, Jennifer R Cochran6, William F Elmquist2, Rachael A Vaubel12, Forest M White3,4,5, Jann N Sarkaria1. 1. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA. 2. Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA. 3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 4. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 5. Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 6. Department of Bioengineering, Stanford University, Stanford, California, USA. 7. Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA. 8. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 9. Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts, USA. 10. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 11. Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA. 12. Department of Laboratory Medicine and Pathology; Mayo Clinic, Rochester, Minnesota, USA. 13. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Abstract
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.
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.
Authors: Rachael A Vaubel; Shulan Tian; Dioval Remonde; Mark A Schroeder; Ann C Mladek; Gaspar J Kitange; Alissa Caron; Thomas M Kollmeyer; Rebecca Grove; Sen Peng; Brett L Carlson; Daniel J Ma; Gobinda Sarkar; Lisa Evers; Paul A Decker; Huihuang Yan; Harshil D Dhruv; Michael E Berens; Qianghu Wang; Bianca M Marin; Eric W Klee; Andrea Califano; Daniel H LaChance; Jeanette E Eckel-Passow; Roel G Verhaak; Erik P Sulman; Terry C Burns; Fredrick B Meyer; Brian P O'Neill; Nhan L Tran; Caterina Giannini; Robert B Jenkins; Ian F Parney; Jann N Sarkaria Journal: Clin Cancer Res Date: 2019-12-18 Impact factor: 12.531
Authors: Kenneth D Aldape; Karla Ballman; Alfred Furth; Jan C Buckner; Caterina Giannini; Peter C Burger; Bernd W Scheithauer; Robert B Jenkins; C David James Journal: J Neuropathol Exp Neurol Date: 2004-07 Impact factor: 3.685
Authors: Amelie Griveau; Giorgio Seano; Samuel J Shelton; Robert Kupp; Arman Jahangiri; Kirsten Obernier; Shanmugarajan Krishnan; Olle R Lindberg; Tracy J Yuen; An-Chi Tien; Jennifer K Sabo; Nancy Wang; Ivy Chen; Jonas Kloepper; Louis Larrouquere; Mitrajit Ghosh; Itay Tirosh; Emmanuelle Huillard; Arturo Alvarez-Buylla; Michael C Oldham; Anders I Persson; William A Weiss; Tracy T Batchelor; Anat Stemmer-Rachamimov; Mario L Suvà; Joanna J Phillips; Manish K Aghi; Shwetal Mehta; Rakesh K Jain; David H Rowitch Journal: Cancer Cell Date: 2018-04-19 Impact factor: 31.743
Authors: Martin van den Bent; Hui K Gan; Andrew B Lassman; Priya Kumthekar; Ryan Merrell; Nicholas Butowski; Zarnie Lwin; Tom Mikkelsen; Louis B Nabors; Kyriakos P Papadopoulos; Marta Penas-Prado; John Simes; Helen Wheeler; Tobias Walbert; Andrew M Scott; Erica Gomez; Ho-Jin Lee; Lisa Roberts-Rapp; Hao Xiong; Earle Bain; Peter J Ansell; Kyle D Holen; David Maag; David A Reardon Journal: Cancer Chemother Pharmacol Date: 2017-10-26 Impact factor: 3.333
Authors: Kutluay Uluc; Prakash Ambady; Matthew K McIntyre; John Philip Tabb; Cymon N Kersch; Caleb S Nerison; Amy Huddleston; Jesse J Liu; Aclan Dogan; Ryan A Priest; Rongwei Fu; Joao Prola Netto; Dominic A Siler; Leslie L Muldoon; Seymur Gahramanov; Edward A Neuwelt Journal: Neurooncol Adv Date: 2022-06-25
Authors: Ghazal Naseri Kouzehgarani; Pankaj Kumar; Susan E Bolin; Edward B Reilly; Didier R Lefebvre Journal: Pharmaceutics Date: 2022-07-12 Impact factor: 6.525
Authors: Kendra A Porath; Michael S Regan; Jessica I Griffith; Sonia Jain; Sylwia A Stopka; Danielle M Burgenske; Katrina K Bakken; Brett L Carlson; Paul A Decker; Rachael A Vaubel; Sonja Dragojevic; Ann C Mladek; Margaret A Connors; Zeng Hu; Lihong He; Gaspar J Kitange; Shiv K Gupta; Thomas M Feldsien; Didier R Lefebvre; Nathalie Y R Agar; Jeanette E Eckel-Passow; Edward B Reilly; William F Elmquist; Jann N Sarkaria Journal: Neurooncol Adv Date: 2022-08-24