MRI biomarkers identify the differential response of glioblastoma multiforme to anti-angiogenic therapy.
BACKGROUND
Although anti-angiogenic therapy (AATx) holds great promise for treatment of malignant gliomas, its therapeutic efficacy is not well understood and can potentially increase the aggressive recurrence of gliomas. It is essential to establish sensitive, noninvasive biomarkers that can detect failure of AATx and tumor recurrence early so that timely adaptive therapy can be instituted. We investigated the efficacy of MRI biomarkers that can detect response to different classes of AATxs used alone or in combination with radiation.


METHODS
Murine intracranial glioma xenografts (NOD/SCID) were treated with sunitinib, VEGF-trap or B20 (a bevacizumab equivalent) alone or in combination with radiation. MRI images were acquired longitudinally before and after treatment, and various MRI parameters (apparent diffusion coefficient, T1w + contrast, dynamic contrast-enhanced [DCE], initial area under the contrast enhancement curve, and cerebral blood flow) were correlated to tumor cell proliferation, overall tumor growth, and tumor vascularity.


RESULTS
Combinatorial therapies reduced tumor growth rate more efficiently than monotherapies. Apparent diffusion coefficient was an accurate measure of tumor cell density. Vascular endothelial growth factor (VEGF)-trap or B20, but not sunitinib, resulted in significant reduction or complete loss of contrast enhancement. This reduction was not due to a reduction in tumor growth or microvascular density, but rather was explained by a reduction in vessel permeability and perfusion. We established that contrast enhancement does not accurately reflect tumor volume or vascular density; however, DCE-derived parameters can be used as efficient noninvasive biomarkers of response to AATx.


CONCLUSIONS
MRI parameters following therapy vary based on class of AATx. Validation of clinically relevant MRI parameters for individual AATx agents is necessary before incorporation into routine practice.
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Shahrzad
S
Jalali
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Caroline
C
Chung
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Warren
W
Foltz
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Kelly
K
Burrell
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Sanjay
S
Singh
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Richard
R
Hill
Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada (S.J., K.B., S.S., G.Z.); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada (C.C., W.F.); Department of Radiation Oncology, University of Toronto, Toronto, Canada (W.F., R.H.); Ontario Cancer Institute, Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Canada (R.H.); Division of Neurosurgery, University of Toronto and Toronto Western Hospital, University Health Network, Toronto, Canada (G.Z.).
Gelareh
G
Zadeh
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000068258:Bevacizumab; D015415:Biomarkers; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007211:Indoles / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D051379:Mice; D011758:Pyrroles / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D000077210:Sunitinib
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D007211:Indoles; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib
MRI biomarker; anti-angiogenic therapies; glioblastoma multiforme (GBM)