4.1.1. Epidermal Growth Factor Receptor (HER2, ERBB2)-Targeting Probes

The human HER2, which is expressed on the cell plasma membrane [102], is a typical molecular marker for breast cancers and a subset of aggressive thyroid cancers [103,104]. HER2 overexpression was found in 44% of FTCs, 18% of PTCs [105], and certain ATCs [106]. Several HER2-specific agents—such as trastuzumab, lapatinib, and pertuzumab—have primarily ameliorated the prognosis in HER2-positive breast cancers [107,108]. Outside of breast cancers and TCs, HER2 is also widely overexpressed in multiple malignancies, including bladder, pancreatic, ovarian, and stomach cancers [109–111]. CUDC-101 (an inhibitor of epidermal growth factor receptor (EGFR), HER2, and histone deacetylase (HDAC)) inhibited tumor growth and metastases in metastatic ATC models [112], and lapatinib (an inhibitor of HER2 and EGFR) overcame the ERK and v-akt murine thymoma viral oncogene homolog 1 (AKT) rebound in PLX4032 resistant TC cells [113]. These studies indicate that HER2 is a potential target for developing theranostic interventions for advanced TCs.

By labeling the HER2-targeting mAb pertuzumab with 89Zr, we have developed the [89Zr]Zr-DFO-pertuzumab and evaluated its diagnostic efficacy in subcutaneous and orthotopic ATC models [114] (Figure 8). ImmunoPET and fluorescence imaging indicated that radiolabeled or fluorescence-labeled HER2 probes are promising for the management of ATCs, which may become helpful tools for image-guided tumor removal or identifying HER2-positive ATCs for HER2-targeted therapies. However, clinical studies are needed for further translation. To facilitate clinical translation and broad clinical use, we have developed a series of novel nanobody-based tracers to delineate HER2 expression. We will test the performance of the tracers in TC models very soon.

**Figure 8.** PET imaging with [89Zr]Zr-DFO-pertuzumab in xenografts (cell line: THJ-16T). (**A**) Maximum intensity projection (MIP) showed the ability of [89Zr]Zr-DFO-pertuzumab for visualizing TCs in an orthotopic model. (**B**) Coronal imaging in an orthotopic model. (**C**) MIP in a subcutaneous model. (**D**) Coronal imaging in a subcutaneous model. Reproduced with permission from [114], copyright 2019 e-Century Publishing Corporation.
