Novel Endometrial Cancer Models Using Sensitive Metastasis Tracing for CXCR4-Targeted Therapy in Advanced Disease

Esperanza Medina-Gutiérrez, María Virtudes Céspedes, Alberto Gallardo, Elisa Rioja-Blanco, Miquel Àngel Pavón, Laura Asensio-Puig, Lourdes Farré, Lorena Alba-Castellón, Ugutz Unzueta, Antonio Villaverde, Esther Vázquez, Isolda Casanova, Ramon Mangues

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Advanced endometrial cancer (EC) lacks therapy, thus, there is a need for novel treatment targets. CXCR4 overexpression is associated with a poor prognosis in several cancers, whereas its inhibition prevents metastases. We assessed CXCR4 expression in EC in women by using IHC. Orthotopic models were generated with transendometrial implantation of CXCR4-transduced EC cells. After in vitro evaluation of the CXCR4-targeted T22-GFP-H6 nanocarrier, subcutaneous EC models were used to study its uptake in tumor and normal organs. Of the women, 91% overexpressed CXCR4, making them candidates for CXCR4-targeted therapies. Thus, we developed CXCR4 + EC mouse models to improve metastagenesis compared to current models and to use them to develop novel CXCR4-targeted therapies for unresponsive EC. It showed enhanced dissemination, especially in the lungs and liver, and displayed 100% metastasis penetrance at all clinically relevant sites with anti-hVimentin IHC, improving detection sensitivity. Regarding the CXCR4-targeted nanocarrier, 60% accumulated in the SC tumor; therefore, selectively targeting CXCR4 + cancer cells, without toxicity in non-tumor organs. Our CXCR4 + EC models will allow testing of novel CXCR4-targeted drugs and development of nanomedicines derived from T22-GFP-H6 to deliver drugs to CXCR4 + cells in advanced EC. This novel approach provides a therapeutic option for women with metastatic, high risk or recurrent EC that have a dismal prognosis and lack effective therapies.

Original languageEnglish
Article number1680
JournalBiomedicines
Volume10
Issue number7
DOIs
Publication statusPublished - 12 Jul 2022

Keywords

  • CXCR4-targeted nanoparticles
  • advanced endometrial cancer
  • animal model
  • metastasis
  • orthotopic model

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