A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma
Year: 2021
Type: article
Abstract: 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.
Source: British Journal of Cancer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Harry J. Lloyd Charitable Trust, Wellcome Trust, Barts Charity, Cancer Research UK, National Institute for Health and Care Research, Royal Society, European Commission, King's Health Partners, Horizon 2020 Framework Programme, Medical Research Council, Engineering and Physical Sciences Research Council, Centre For Medical Engineering, King’s College London
Awards: G1210638227, G1247657515, G1297927785, G1481929885, G2417159676, G2869883816, G3158328457, G3291143030, G3345895242, G3454841734, G3634344204, G3799972128, G5045220161, G526393511, G5413057595, G5841612952, G5848717864, G6552948620, G6684864072, G6868811358, G7242454566, G7796927425, G7942143898, The role of RNA Binding Proteins (RBPs) in breast cancer progression and metastasis, G961285871
OpenAlex ID: W3175161237