PURPOSE: To investigate alphavbeta3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma. MATERIALS AND METHODS: Human BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an alphavbeta3-integrin-targeted fluorescent probe. The alphavbeta3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ss3 -integrin expression, CD31 -microvascular density, Ki-67 -proliferation). RESULTS: The alphavbeta3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98+/-2.22 to 1.67+/-1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60+/-6.51 to 3.67+/-1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ss3: 0.20+/-0.02 vs. 0.39+/-0.05; p = 0.008) and microvascular density (CD31: 119+/-15 vs. 292+/-49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107+/-42 mm3; control +112+/-44mm3, p = 0.841). In vivo blocking studies with alphavbeta3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe. CONCLUSIONS: alphavbeta3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria.
- Kazmierczak, P. M.
- Burton, N. C.
- Keinrath, G.
- Hirner-Eppeneder, H.
- Schneider, M. J.
- Eschbach, R. S.
- Heimer, M.
- Solyanik, O.
- Todica, A.
- Reiser, M. F.
- Ricke, J.
- Cyran, C. C.
