Human epidermal growth factor receptor 2 (HER2) is a biomarker in breast cancer, and its overexpression is required to initiate therapies using HER2-targeted antibodies. Although trastuzumab is one of the most effective therapeutic antibodies in HER2-overexpressing breast cancer, a significant number of patients do not benefit from this therapy due to inherent or acquired resistance mechanisms. One reported mechanism of resistance is the steric hindering effect caused by the polymeric complex formed between hyaluronan and CD44, thus preventing trastuzumab from binding to HER2. Hyaluronan/CD44 contributes as an obstacle for trastuzumab to bind HER2, but it is also involved in HER2 internalization. In this study, we used zirconium-89 (89 Zr)-labeled trastuzumab immunoPET to investigate whether degradation of hyaluronan can resensitize HER2-overexpressing breast cancer cells to trastuzumab. Targeted degradation of endogenously produced hyaluronan and inhibition of its synthesis were achieved by treating trastuzumab-resistant JIMT1 breast cancer cells with hyaluronidase (HLX) and 4methylumbelliferone (4MU). The 4MU/HLX treatment reduced HER2 internalization by depleting hyaluronan/CD44 and the caveolin-1 (CAV1) endocytic protein, resulting in enhanced membrane-*

The specificity of antibodies for antigens overexpressed or uniquely expressed in tumor cells makes them ideal candidates in the development of bioconjugates for tumor imaging. Molecular imaging can aid clinicians in the diagnosis of gastric tumors and in selecting patients for therapies targeting receptors with a heterogeneous intratumoral or intertumoral expression. Antibodies labeled with an imaging radiometal can be used to detect primary tumors and metastases using whole-body positron emission tomography (PET) or single photon emission computed tomography (SPECT), both during diagnosis and monitoring disease response. Conjugated with fluorescent dyes, antibodies can image tumors by targeted optical imaging. This review provides an overview of the most recent advances in the use of antibodies labeled with radiometals or conjugated with fluorescent dyes for gastric cancer imaging.

The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the 89 Zrlabeled or 64 Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple-or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.