AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.
Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
Batchelor
Tracy T
TT
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. tbatchelor@partners.org
Sorensen
A Gregory
AG
di Tomaso
Emmanuelle
E
Zhang
Wei-Ting
WT
Duda
Dan G
DG
Cohen
Kenneth S
KS
Kozak
Kevin R
KR
Cahill
Daniel P
DP
Chen
Poe-Jou
PJ
Zhu
Mingwang
M
Ancukiewicz
Marek
M
Mrugala
Maciej M
MM
Plotkin
Scott
S
Drappatz
Jan
J
Louis
David N
DN
Ivy
Percy
P
Scadden
David T
DT
Benner
Thomas
T
Loeffler
Jay S
JS
Wen
Patrick Y
PY
Jain
Rakesh K
RK
D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D001932:Brain Neoplasms / Q000098:blood supply / Q000150:complications / Q000188:drug therapy*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000097:blood / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000098:blood supply / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009364:Neoplasm Recurrence, Local / Q000150:complications / Q000188:drug therapy; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D007211:Indoles
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005346:Fibroblast Growth Factors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C515255:CXCL12 protein, human; C500926:cediranib; D007211:Indoles