Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [89Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model

Purpose Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([ 89 Zr]T) binding/uptake. Procedures The...

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Published inMolecular imaging and biology Vol. 17; no. 5; pp. 697 - 703
Main Authors Wimana, Zéna, Gebhart, G., Guiot, T., Vanderlinden, B., Morandini, R., Doumont, G., Sherer, F., Van Simaeys, G., Goldman, S., Ghanem, G., Flamen, P.
Format Journal Article
LanguageEnglish
Published New York Springer US 01.10.2015
Springer Nature B.V
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Summary:Purpose Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([ 89 Zr]T) binding/uptake. Procedures The effect of N -acetylcysteine (NAC) and MUC4 knockdown/stimulation on [ 89 Zr]T binding/uptake were evaluated in MCF7(HER2−), BT474 and SKBr3(HER2+/MUC4−), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis. Results Significant increases in [ 89 Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5 %) and exposure to NAC (62.8 ± 19.4 %). Compared to controls, mice treated with NAC showed a significant increase in [ 89 Zr]T uptake in MUC4 tumors on microPET-CT (SUV mean (18.3 ± 4.7 %), SUV max (41.7 ± 8.4 %)) and individual organ counting (37.3 ± 18.3 %). In contrast, no significant differences were observed in SKBr3. Conclusion NAC can enhance [ 89 Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.
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ISSN:1536-1632
1860-2002
DOI:10.1007/s11307-015-0840-x