A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma
| العنوان: | A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma |
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| المؤلفون: | Eva Crosas-Molist, Lena Boehme, Faraz K. Mardakheh, Bruce Fanshawe, Jose L. Orgaz, Gilbert O. Fruhwirth, Irene Rodriguez-Hernandez, Victoria Sanz-Moreno, Oscar Maiques, Gaia Cantelli, Alessia Volpe |
| المساهمون: | Cancer Research UK, Worldwide Cancer Research, Royal Society (UK), Fundación Alfonso Martín Escudero, European Commission, Fundación Ramón Areces, Department of Health & Social Care (UK), National Institute for Health Research (UK), NIHR Biomedical Research Centre (UK) |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname British Journal of Cancer BRITISH JOURNAL OF CANCER |
| بيانات النشر: | Springer Nature, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Cancer Research, RHOA, INVASION, GEFS, Cell morphology, Mass Spectrometry, Metastasis, Mice, Y-27632, 0302 clinical medicine, Cell Movement, Medicine and Health Sciences, Skin cancer, Protein Interaction Maps, Neoplasm Metastasis, Melanoma, rho-Associated Kinases, 0303 health sciences, biology, Drug discovery, CANCER, Oncology, 030220 oncology & carcinogenesis, RHO-KINASE, Signal Transduction, MIGRATION, INHIBITION, Article, 03 medical and health sciences, In vivo, GAPS, Cell Line, Tumor, medicine, Animals, Humans, Cancer models, Protein Kinase Inhibitors, 030304 developmental biology, Myosin Type II, business.industry, Biology and Life Sciences, Computational Biology, Cancer, PROFILES, medicine.disease, Xenograft Model Antitumor Assays, Cancer cell, Cancer research, biology.protein, TRANSLATION, rhoA GTP-Binding Protein, business, Ex vivo |
| الوصف: | © The Author(s) 2021. [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. GOF’s lab was supported by Cancer Research UK [C48390/A21153], Worldwide Cancer Research [16-1153], and King’s Health Partners [King’s Medical Research Trust Joint Research Committee studentship to A.V.]. B.F. was supported by a King’s Health Partners studentship to V.S.M. and G.O.F. V.S.M.’s lab was supported by Cancer Research UK [C33043/A12065] and [C33043/A24478] (V.S.M., E.C.M., J.L.O., L.B. and GC), the Royal Society [RG110591] (V.S.M.), The Harry J. Lloyd Charitable Trust (J.L.O. and V.S.M.), the Barts Charity (V.S.M., J.L.O., O.M., I.R.H. and E.C.M.), the Fundacion Alfonso Martin Escudero and Marie Sklodowska-Curie Action [H2020-MSCA-IF-2014-EF-ST] (I.R.H.), and Fundacion Ramon Areces (E.C.M.). F.M. was supported by an MRC Career Development Award (MR/P009417/1). This work was further supported by the Department of Health (DoH) via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to King’s Health Partners, and the Wellcome/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z]. Views expressed are those of the authors and not necessarily those of the NHS, NIHR or DoH. |
| وصف الملف: | application/pdf |
| تدمد: | 0007-0920 1532-1827 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0245a51b1650d282bfda2f05b9dbaede http://hdl.handle.net/10261/264785 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0245a51b1650d282bfda2f05b9dbaede |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00070920 15321827 |
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