Abstract 4924: Mucolytic drug N-Acetylcystein improves 89Zr-trastuzumab HER2-immunoPET imaging by restoring accessibility to HER2 hampered by membrane mucin overexpression in a HER2 positive MUC4 overexpressing xenograft mouse model

Abstract

Abstract 89Zr-trastuzumab, a 89-Zirconium radiolabeled anti-HER2 monoclonal antibody, has been shown appropriate to enable positron emission tomography (PET) imaging of HER2 positive lesions in breast cancer (BC) patients. Binding of 89Zr-trastuzumab to the HER2 receptor, a prerequisite could be undermined by one of the postulated resistance mechanisms to trastuzumab, i.e. the interference of cell membrane glycoproteins mucins. This study aimed to assess whether mucolytic drug N-Acetylcystein (NAC) could enhance the uptake of 89Zr-trastuzumab in a HER2 positive and MUC4 overexpressing xenograft mouse model. Materials & Methods: Trastuzumab was first coupled with the chelate N-succinyl-desferal ester, subsequently N-SucDF-trastuzumab was radiolabelled with 89Zr-oxalate in a HEPES buffered solution and purified by size exclusion chromatography. The impact of NAC on 89Zr-trastuzumab PET was studied in a dual model xenograft generated by s.c. inoculation of HER2+/MUC4- SKBr3 and JIMT1 HER2+/MUC4- BC cell lines, with the latter overexpressing MUC4. Mice were treated with NAC p.o. during 6 days. Body distribution and uptake of the tracer were measured 1) by in vivo PET/CT imaging and by 2)ex vivo tissue analysis. Results: In mice treated with NAC, there was a significant increase of the Standardized Uptake Value (SUV) mean, SUVmax and SUV Volume Histogram (SVH) in the MUC4 overexpressing tumors compared to the control group. This was not the case for MUC4 negative SKBR3 tumors. Furthermore, ex vivo body distribution data supported these results with a significant increase of radioactivity uptake in the MUC4 positive tumors and no change in non-tumoral tissues Conclusion: N-Acetylcysteine may be an interesting drug to improve the accessibility of trastuzumab to its receptors, HER2, by affecting mucin masking. Note: This abstract was not presented at the meeting. Citation Format: Zena Wimana, Geraldine Gebhart, Renato Morandini, Patrick Flamen, Ghanem Ghanem. Mucolytic drug N-Acetylcystein improves 89Zr-trastuzumab HER2-immunoPET imaging by restoring accessibility to HER2 hampered by membrane mucin overexpression in a HER2 positive MUC4 overexpressing xenograft mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4924. doi:10.1158/1538-7445.AM2014-4924