Positron Emission Tomography (PET) of Breast Cancer Heterogeneous for HER2 and EGFR Using Bispecific Radioimmunoconjugates

Download or read book Positron Emission Tomography (PET) of Breast Cancer Heterogeneous for HER2 and EGFR Using Bispecific Radioimmunoconjugates written by Yongkyu Kwon and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The human epidermal growth factor receptor-2 (HER2) is overexpressed in 15-20% of breast cancer (BC) and is the target for immunotherapy with trastuzumab, pertuzumab, and trastuzumab-emtansine (T-DM1). Despite improvements in survival, resistance to HER2-targeted therapies remains a major problem. One resistance mechanism is loss of HER2 and increased EGFR. Additionally, intratumoral HER2 heterogeneity is correlated with a poor response to trastuzumab. The hypothesis was that novel bispecific radioimmunoconjugates (bsRICs) are capable of permit molecular imaging of both EGFR and HER2 receptors simultaneously with positron emission tomography (PET) and deliver more radioactivity to the tumor especially in the presence of receptor heterogeneity. BsRICs was developed by chemically linking trastuzumab Fab (anti-HER2) to human EGF through a 24-mer polyethylene glycol (PEG24) spacer, and radiolabeled with 64Cu. 64Cu-NOTA-Fab-PEG24-EGF demonstrated the ability to specifically bind to EGFR or HER2 both in vitro and in vivo, and exhibited prolonged blood circulation than monospecific agents in mice. PET imaging was performed on NOD-SCID mice bearing tumor xenografts expressing EGFR, HER2, or both receptors. Tumors were clearly visualized by microPET/CT imaging, and biodistribution studies showed significantly better tumor uptake for bsRICs in tumor xenograft expressing both receptors. Human cancer xenograft mouse models with heterogeneous levels of HER2 and EGFR was established by subcutaneous inoculation of mixtures of SK-OV-3 cells and MDA-MB-468 cells. These BC xenografts were more clearly visualized by microPET/CT, and bsRICs exhibited higher tumor uptake and lower degree of heterogeneous uptake than monospecific agents. These results suggest that bsRICs may be useful for imaging of HER2-positive heterogeneous BC consisting of EGFR-positive subpopulations. Thus, bsRICs will be able to address the challenge of HER2 intratumoral heterogeneity in BC.