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Kazmierczak, Philipp M.; Todica, Andrei; Gildehaus, Franz-Josef; Hirner-Eppeneder, Heidrun; Brendel, Matthias; Eschbach, Ralf S.; Hellmann, Magdalena; Nikolaou, Konstantin; Reiser, Maximilian F.; Wester, Hans-Jürgen; Kropf, Saskia; Rominger, Axel; Cyran, Clemens C. (2016): ⁶⁸Ga-TRAP-(RGD)₃ Hybrid Imaging for the In Vivo Monitoring of α (v)β₃-Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer.
In: PLOS One 11(12), e0168248
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Abstract

Objectives: To investigate Ga-68-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of alpha(v)beta(3)-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 Ga-68-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, VOlmaxtumor/VOlmeanmuscie) 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 (alpha(v)beta(3)-integrin, microvascular density CD31, proliferation Ki-67, apoptosis TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results: Ga-68-TRAP-(RGD)(3) binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (ATBRfollow-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 (Delta TBRvolumetherapy 134 77 pL, AvoluMecontrol 132 56 pL, p = 1.000). Immunohistochemistry revealed a significant reduction of a,133-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: Ga-68-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of a,133-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer.