Abstract
BackgroundThe goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[11C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.MethodsMMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[11C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[11C]PAQ radiotracer uptake and therapy response biomarkers.ResultsThe (R)-[11C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[11C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.ConclusionsThe results of this study are promising. However, additional studies are necessary before (R)-[11C]PAQ can be approved as a predictive radiotracer for cancer therapy response.
Highlights
The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)4-quinazolineamine ((R)-[Carbon-11 labeled-N-(4-bromo-2-fluorophenyl)-6-methoxy7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine (11C]PAQ)) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models
We have previously described the synthesis and carbon-11 labeling of PAQ to yield (R)-[11C]PAQ [19] and demonstrated that the radiotracer uptake correlated with high Vascular endothelial growth factor receptor (VEGFR-2) expression in primary tumors and during metastasis development [20]
The current study aimed to examine the capability of using the (R)-[11C]PAQ VEGFR-2-targeting for monitoring anticancer treatment in the MMTV-PyMT/FVB (PyMT) transgenic mouse breast cancer model
Summary
The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)4-quinazolineamine ((R)-[11C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models. Angiogenesis is driven by potent pro-angiogenic factors and signaling molecules, including growth factors and growth factor receptors [3]. One of the most prominent of these is vascular endothelial growth factor (VEGF)A, known as vascular permeability factor [4]. VEGFA binds with both VEGFR-1 and VEGFR-2 receptors, it is commonly agreed that VEGFR2 is the key mediator of the mitogenic, angiogenic, and microvascular permeability-enhancing effects of VEGF [5]. The overexpression of VEGF/VEGFR-2 by tumor endothelium is associated with increased angiogenesis, metastatic spread of tumor cells, and with poor prognosis in cancer patients [6]
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