title: Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape.
abstract: Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy--characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology--without a second wave of angiogenesis.
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital & Massachusetts Institute of Technology, Boston, Massachusetts 02114, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.forename: Walid S
authors.initials: WS
authors.lastname: Kamoun
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazlollahi
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Andronesi
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: E Tessa
authors.initials: ET
authors.lastname: Hedley-Whyte
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Sorensen
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009364:Neoplasm Recurrence, Local; D011799:Quinazolines / Q000627:therapeutic use*; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011799:Quinazolines; C500926:cediranib; D007211:Indoles