Monitoring the longitudinal intra-tumor physiological impulse response to VEGFR2 blockade in breast tumors using DCE-CT.
OBJECTIVE
The purpose of this study was to quantify and model the longitudinal intra-tumor physiological response to a single dose of a monoclonal antibody specific to the VEGFR2 using dynamic contrast-enhanced CT.


METHODS
Dynamic contrast-enhanced CT imaging was performed on athymic nude mice bearing xenograft VEGF-transfected MCF-7 tumors (MCF7(VEGF)) to quantify intra-tumor physiology pre- and post-injection (days 2, 7, and 14) of a nonspecific (IgG1, controls) and specific (DC101, treated) monoclonal antibody targeting VEGFR2. Parametrical maps of tumor physiology-perfusion (F), permeability surface area (PS), fractional plasma (f(p)), and interstitial space (f (is))-were obtained at four time points over a 2-week period.


RESULTS
A temporal multistage recovery process whereby a decoupling of the fractional change in physiological parameters (f (p), F) was observed when comparing treated to control tumors: f (p) and perfusion decreased by a combined 27% (P < 0.01) and 65% (P < 0.01) on day 2, while only perfusion remained reduced by 46% (P < 0.01) on day 7. Intra-tumor heterogeneity defined by the change in variance of perfusion decreased on days 2 and 7; no change in the variance of f(p) was observed. Analysis based on a mathematical model linking perfusion and vascular morphology indicates that a decrease in f(p) and perfusion was consistent with a reduction in blood vessel radius, followed by an increase in the vascular radius and tortuosity resulting in the decoupling of f(p) and perfusion before returning to control levels.


CONCLUSIONS
Inhibiting VEGFR2 activity results in a temporal decoupling of physiological parameters, which can be explained by a combination of morphological changes influencing perfusion. Such a decoupling has the potential to significantly impact the delivery of pharmaceuticals and oxygen within solid tumors, critical factors in combined anti-angiogenic and radio- and chemotherapies.
Stantz
Keith M
KM
School of Health Sciences, Division of Medical Physics, Purdue University, West Lafayette, IN 47907-2051, USA. kstantz@purdue.edu
Cao
Minsong
M
Cao
Ning
N
Liang
Yun
Y
Miller
Kathy D
KD
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010953:Plasma Volume; D014057:Tomography, X-Ray Computed / Q000379:methods*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D040301:Vascular Endothelial Growth Factor Receptor-2