A preclinical pipeline to evaluate migrastatics as therapeutic agents in metastatic melanoma

• Published in: British journal of cancer 2021-08, Vol.125 (5), p.699-713
• Main Authors: Maiques, Oscar, Fanshawe, Bruce, Crosas-Molist, Eva, Rodriguez-Hernandez, Irene, Volpe, Alessia, Cantelli, Gaia, Boehme, Lena, Orgaz, Jose L., Mardakheh, Faraz K., Sanz-Moreno, Victoria, Fruhwirth, Gilbert O.
• Format: Article
• Language: English
• Subjects: 631/154; 692/4028/67/1813; 692/4028/67/322; 692/4028/67/70; Animals; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Cell Line, Tumor; Cell Movement - drug effects; Computational Biology - methods; Cytology; Drug development; Drug Resistance; Epidemiology; Humans; Male; Mass Spectrometry; Melanoma; Melanoma - drug therapy; Melanoma - metabolism; Metastases; Metastasis; Mice; Molecular Medicine; Myosin; Myosin Type II - metabolism; Neoplasm Metastasis; Oncology; Protein Interaction Maps; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Rho-associated kinase; rho-Associated Kinases - metabolism; rhoA GTP-Binding Protein - metabolism; RhoA protein; Signal Transduction - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01442-6

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.