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

Oscar Maiques,Gaia Cantelli,Gilbert O Fruhwirth,Jose L Orgaz,Faraz K Mardakheh,Bruce Fanshawe,Lena Boehme,Victoria Sanz-Moreno,Irene Rodriguez-Hernandez,Alessia Volpe,Eva Crosas-Molist

doi:10.1038/s41416-021-01442-6

Abstract

BackgroundMetastasis 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.MethodsWe 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.ResultsUnbiased 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.ConclusionsWe 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.

Highlights

Metastasis is a hallmark of cancer and responsible for most cancer deaths
We present hierarchical clustering according to expression level changes of 58 guanine nucleotide exchange factors (GEFs), the major Rho GTPases, 704 Fig. 1 Cancer patient database mining to identify genes involved in melanoma progression. a Unbiased REACTOME pathway enrichment analysis of differentially expressed genes in metastatic versus primary melanoma samples from the The Cancer Genome Atlas (TCGA) database
Our aim was to demonstrate a systematic ‘pipeline’ approach for the development of migrastatic drugs. We exemplified this pipeline in the context of melanoma, a skin cancer characterised by its high propensity to metastasise.[7]

Summary

Introduction

Migrastatics were defined as drugs interfering with all modes of cancer cell invasion and cancers’ ability to metastasise. An anti-metastatic prostate cancer drug, apalutamide, was recently approved by the FDA involving the new endpoint of ‘metastasisfree survival’, measuring the length of time that tumours did not spread to other parts of the body or that death occurred after starting treatment.[2] Recently, we defined a new class of drugs that we coined ‘migrastatics’, and which would comprise drugs interfering with all modes of cancer cell invasion and with their ability to metastasise.[3,4] Migrastatics have the potential to be of particular value for the treatment of cancers with the propensity to metastasise early. Patients suffering from malignant advanced melanoma have a very poor prognosis.[6,7]

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Conclusion