Enhancing TDM1 Therapeutic Efficacy through HER2 Modulation and Imaging in Gastric Tumors
Presenter(s)
Abbey Zidel
Faculty research mentor
Patricia Ribeiro Pereira
Presentation session
12:00PM - 1:00PM: Lightning Talks 2 (BH 150)
Acknowledgments
I would like to thank Emma L. Brown, Na-Keysha Berry, Sandeep Surendra Panikar, Shayla Shmuel, and Patricia Ribeiro Pereira for their contributions to this work. We thank the Cyclotron & Nuclear Pharmacy at WUSTL for producing Cu-64, and the WUSTL Small Animal Imaging Facility for their assistance with PET imaging acquisition. This research was supported by internal funds provided by the Mallinckrodt Institute of Radiology and NIH (R01 CA244233-01A1).
Abstract or Description
Human epidermal growth factor receptor 2, HER2, is a membrane receptor often targeted in cancer treatment, and it is overexpressed in some gastric cancers. Trastuzumab emtansine (TDM1) is an antibody-drug conjugate (ADC) that binds HER2, targeting HER2-positive (HER2+) cells with a chemotherapeutic agent, emtansine. HER2+ gastric cancer has demonstrated resistance to TDM1 treatment, so we investigated the use of statin and neratinib to enhance TDM1 efficacy in an NCIN87 gastric tumor model. Statins are cholesterol-depleting drugs known to upregulate HER2 at the cell surface, and neratinib is an irreversible tyrosine kinase inhibitor known to increase HER2 internalization and degradation. We used statins to enhance HER2 membrane density, allowing TDM1 to effectively bind, followed by neratinib treatment for effective internalization of HER2-bound TDM1. Immunofluorescence imaging confirmed an enhancement of cell-surface and internalized HER2 after statin and neratinib incubations, respectively. A pHrodo assay demonstrated enhanced trastuzumab internalization after statin/neratinib incubation. Additionally, western blots indicated downregulated HER2 signaling with TDM1/statin/neratinib treatment. To validate this therapeutic potential, an in vivo study in nu/nu mice was performed. Tumor volume and mouse weight were monitored, and both pre- and post-therapy PET/CT images were collected using copper-64 labeled trastuzumab (64Cu-trastuzumab). This non-invasive imaging technique accurately reflected the decrease in HER2 tumoral expression associated with a decrease in tumor volume which was sustained in the TDM1/statin/neratinib group. This work demonstrates TDM1 therapeutic enhancement through a TDM1/statin/neratinib treatment in the NCIN87 gastric tumor model in cells and mice. The treatment effects can be successfully monitored and predicted using 64Cu-trastuzumab PET/CT imaging.