Objectives: To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
Materials And Methods: Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvß3-integrin, microvascular density-CD31, proliferation-Ki-67, apoptosis-TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12).
Results: 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (ΔTBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 μL, Δvolumecontrol 132±56 μL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvß3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group.
Conclusions: 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167276 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168248 | PLOS |
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