Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival

Purpose EphA2 overexpression is frequently observed in endometrial cancers, and is predictive of poor clinical outcome. Here, we utilize 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 (MMAF). 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 demonstrated 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 to controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The anti-tumor 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 demonstrate substantial anti-tumor activity.

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EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma

Lee

Stone

Lee

et al. 2010

Clinical Cancer Research

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Chemoresistance and targeted therapies in ovarian and endometrial cancers

2016

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Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

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Dual inhibition of RNAi therapeutic miR-26a-5p targeting cMet and immunotherapy against EGFR in endometrial cancer treatment

Liu¹,

Cai²,

Chang³

2021

Ann Transl Med

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Background: Precise prediction of drug combination targeting tumor cells effectively is a crucial challenge for tumor therapy, especially for endometrial cancer (EC). Considering the resistance, crosstalk that occurs between the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMet) and epidermal growth factor receptor (EGFR), and their indispensable influence on the occurrence of EC, this study aimed to explore a novel therapeutic approach for EC treatment through blocking cMet and EGFR simultaneously.Methods: In the present study, the expression of miR-26a-5p in EC cell lines was detected using quantitative real-time polymerase chain reaction assay. The potential role of miR-26a-5p in the development of EC was examined using cell counting kit assay, 5-ethynyl-2'-deoxyuridine staining, wound healing assay, and cell apoptosis staining assay. Subsequently, the effect of upregulated miR-26a-5p in vivo was confirmed on a xenograft model. Luciferase reporter assay and Western blot analysis were performed to verify the relation between miR-26a-5p and cMet. Furthermore, the dual therapeutic effect of miR-26a-5p and EGFR monoclonal antibody cetuximab was confirmed in vivo and in vitro. Results:The results indicated that miR-26a-5p expression significantly reduced in EC cell lines compared with the normal endometrial cell line. Furthermore, the overexpression of miR-26a-5p inhibited the progression of EC, including cell migration, cell proliferation, and cell apoptosis in vivo and in vitro.Subsequently, mir-26a-5p regulated the expression of cMet and the downstream the hepatocyte growth factor (HGF)/cMet pathway, thus exerting an inhibitory effect on EC cells. In addition, the study also demonstrated that the upregulation of miR-26a-5p could significantly enhance the inhibitory effect of cetuximab compared with the use of cetuximab alone in vivo and in vitro.Conclusions: RNAi therapeutic miR-26a-5p suppressed the progression of EC through regulating the cMet/HGF pathway. The dual therapy using RNA interference and neutralizing antibody simultaneously blocked tumor targets, including cMet and EGFR, thus providing a novel approach for overcoming the resistance to the inhibitors against a single target in EC treatment.

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Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival

Cited by 4 publications

References 21 publications

EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma

EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma

Chemoresistance and targeted therapies in ovarian and endometrial cancers

Dual inhibition of RNAi therapeutic miR-26a-5p targeting cMet and immunotherapy against EGFR in endometrial cancer treatment

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