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Título: | A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma |
Autor: | Maiques, Óscar; Fanshawe, Bruce; Crosas-Molist, Eva; Rodriguez-Hernandez, Irene; Volpe, Alessia; Cantelli, Gaia; Boehme, Lena; Orgaz, José L. CSIC ORCID; Mardakheh, Faraz K.; Sanz-Moreno, Victoria; Fruhwirth, Gilbert O. | Palabras clave: | Cancer models Drug discovery Metastasis Skin cancer |
Fecha de publicación: | 2021 | Editor: | Springer Nature | Citación: | British Journal of Cancer 125: 699-713 (2021) | Resumen: | [Background]: Metastasis is a hallmark of cancer and responsible for most cancer deaths. Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and thus cancers’ ability to metastasise. First anti-metastatic treatments have recently been approved. [Methods]: We used bioinformatic analyses of publicly available melanoma databases. Experimentally, we performed in vitro target validation (including 2.5D cell morphology analysis and mass spectrometric analysis of RhoA binding partners), developed a new traceable spontaneously metastasising murine melanoma model for in vivo validation, and employed histology (haematoxylin/eosin and phospho-myosin II staining) to confirm drug action in harvested tumour tissues. [Results]: Unbiased and targeted bioinformatic analyses identified the Rho kinase (ROCK)-myosin II pathway and its various components as potentially relevant targets in melanoma. In vitro validation demonstrated redundancy of several RhoGEFs upstream of RhoA and confirmed ROCK as a druggable target downstream of RhoA. The anti-metastatic effects of two ROCK inhibitors were demonstrated through in vivo melanoma metastasis tracking and inhibitor effects also confirmed ex vivo by digital pathology. [Conclusions]: We proposed a migrastatic drug development pipeline. As part of the pipeline, we provide a new traceable spontaneous melanoma metastasis model for in vivo quantification of metastasis and anti-metastatic effects by non-invasive imaging. | Descripción: | © The Author(s) 2021. | Versión del editor: | http://dx.doi.org/10.1038/s41416-021-01442-6 | URI: | http://hdl.handle.net/10261/264785 | DOI: | 10.1038/s41416-021-01442-6 | ISSN: | 0007-0920 | E-ISSN: | 1532-1827 |
Aparece en las colecciones: | (IIBM) Artículos |
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A_preclinical_pipeline_Maiques_PV_Art2021.pdf | 6,48 MB | Adobe PDF | Visualizar/Abrir |
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