Abstract
P1055
Introduction: Trastuzumab emtansine (TDM1) is an antibody-drug conjugate (ADC) that binds HER2 (human epidermal growth factor receptor 2) — a membrane receptor overexpressed in gastric cancer. While TDM1 effectively treats HER2-positive (HER2+) breast cancer, clinical trials failed to demonstrate the efficacy of TDM1 in treating gastric cancer. Statins, cholesterol-depleting drugs, increase cell-surface HER2 density in ways that enhance TDM1 efficacy in gastric tumors. However, resistance occurs in gastric tumors treated with TDM1/statin approximately 40-50 days after therapy. In an attempt to reverse drug resistance in gastric cancer, this study tested TDM1/statin in combination with the irreversible tyrosine kinase inhibitor neratinib. To monitor response to therapy, we use HER2-targeted PET imaging.
Methods: Animals: NCIN87 cancer cells were implanted into female (n=6) and male (n=6) nu/nu mice. Treatments: Mice were administered TDM1 (5mg/kg, intravenously, single dose), lovastatin (4.15mg/kg, oral gavage, 2 consecutive days), neratinib (20mg/kg, oral gavage, 5 consecutive days). Imaging: HER2-targeted positron emission tomography (PET) was performed using trastuzumab radiolabeled with copper-64 (64Cu-trastuzumab) pre- and post-therapy. Western blot and immunofluorescence analysis: HER2 cellular localization and HER2-mediated signaling was determined by immunofluorescence and Western blot assays. Trastuzumab-mediated HER2 internalization was monitored using pHrodo and endosomal immunofluorescent markers.
Results: Immunofluorescence demonstrated increased HER2 membrane localization in statin-treated cells, and increased HER2 internalization in neratinib- or neratinib/statin-treated cells when compared to the control group (Fig. 1). Cells treated with TDM1/neratinib/statin demonstrated a downregulation in total HER2 and HER2-mediated oncogenic signaling. The potential of neratinib/statin to enhance TDM1 efficacy was further validated in a therapeutic study. The sustained therapeutic response in TDM1/neratinib/statin cohorts was accompanied by a decrease in tumor volume regression. HER2-PET non-invasive imaging was able to monitor response to treatment (Persuasive data).
Conclusions: This work indicates that a single dose of TDM1/neratinib/statin combination enhances TDM1 efficacy in gastric tumors and is a more effective treatment than any other combination of those drugs, or any of those drugs administered alone. PET-CT imaging was successful at monitoring and predicting the response of gastric tumors to TDM1 therapy.
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