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EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma
Jeong-Won Lee1, Rebecca L Stone, Sun Joo Lee
1Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Purpose:
EphA2 overexpression is frequently observed in endometrial cancers and is predictive of poor clinical outcome. Here, we use an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor monomethylauristatin F.
Experimental Design:
EphA2 expression was examined in endometrial cancer cell lines by Western blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models.
Results:
EphA2 was expressed in the Hec-1A and Ishikawa cells but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2-positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays showed that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86% to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared with controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The antitumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells.
Conclusions:
The preclinical data for endometrial cancer treatment using MEDI-547 show substantial antitumor activity.
Insights
The antibody drug conjugate MEDI-547 shows significant preclinical antitumor activity in endometrial cancer models by targeting EphA2. This targeted therapy reduced tumor growth, decreased metastasis, and induced cancer cell apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- EphA2 overexpression is a common biomarker in endometrial cancers, correlating with poor patient prognosis.
- Targeting EphA2 presents a potential therapeutic strategy for endometrial cancer.
Purpose of the Study:
- To evaluate the preclinical efficacy of MEDI-547, an antibody drug conjugate targeting EphA2, in endometrial cancer models.
- To assess the impact of MEDI-547 on tumor growth, apoptosis, and metastasis in vitro and in vivo.
Main Methods:
- Western blot analysis to confirm EphA2 expression in endometrial cancer cell lines.
- In vitro assays to assess antibody drug conjugate internalization, cytotoxicity, and apoptosis induction.
- In vivo orthotopic mouse models to evaluate tumor growth inhibition and metastasis reduction.
Main Results:
- MEDI-547 demonstrated EphA2-specific internalization and degradation in EphA2-positive endometrial cancer cells.
- In vitro studies showed MEDI-547 significantly reduced cell viability and increased apoptosis.
- In vivo studies in orthotopic models resulted in 86-88% tumor growth inhibition and reduced distant metastasis.
Conclusions:
- Preclinical data indicate substantial antitumor activity of MEDI-547 in endometrial cancer.
- MEDI-547 represents a promising targeted therapy for endometrial cancer with potential to inhibit proliferation and induce apoptosis.
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