Anti-ICAM1 monoclonal antibody, clone 252028

Metastatic spread is the leading cause for cancer-related mortality, with the lungs being a major site for metastatic seeding. Available therapies for patients with metastatic disease are extremely limited. Therefore, there is a desperate need for new strategies to prevent or limit metastatic dissemination and treat existing metastases. The metastatic cascade is highly complex and is affected by multiple factors related to both tumor cells themselves and the microenvironment in the future site of metastasis. We hypothesized that modifying the lung microenvironment by blocking central ubiquitous signals may affect metastatic seeding in the lungs. Given the high basal levels of the Receptor for Advanced Glycation End products (RAGE) in the pulmonary tissue, and its pro-inflammatory properties, we investigated the consequences of interfering with its ligand; High Mobility Group Box 1 (HMGB1). To this end, we tested the effect of Carbenoxolone, an HMGB1 antagonist, on primary tumor growth and metastatic progression in several murine tumor models. We show that antagonizing HMGB1 prevents the adhesion and colonization of cancer cells in the lungs through the reduction of their adhesion and cell-cell interaction both in vitro and in vivo. We demonstrated that these activities are mediated by downregulation of the adhesion molecule Intercellular Adhesion Molecule 1 (ICAM1) and ultimately result in reduced metastatic burden. Carbenoxolone decreases significantly lung metastases formation and can be used potentially as prophylactic therapy for metastatic diseases.

Background: Understanding of different severity of atherosclerotic lesions using protein protein interaction network (PPI) analysis of differentially expressed genes (DEGs) may identify differing underlying molecular & cellular mechanisms. Methods: DEGs were obtained for coronary artery disease (CAD) and different severities of CAD including six each with single vessel disease (SVD) and triple vessels disease (TVD) patients compared with age-matched six controls. The DEGs were subjected to form PPI networks on STRINGv10.0. The PPI network was analysed and visualised on Cytoscape v3.4.0. The hub nodes (genes) of PPI network were identified and subsequently analysed for biological processes using biological network of gene ontology (BiNGO) and ClueGO. DEGs constructed PPI network were also analysed for biological processes and pathways using ClueGO and Kyto encyclopedia of gene and genome (KEGG.) Results: PPI network analysis revealed hub genes APOA1 and CFTR with high degree and betweenness centrality for CAD. Similarly, SRC and ICAM1 genes were identified for SVD and ESR1 and HNF1A had highest degree and betweenness centrality for TVD. The biological processes distinguishing CAD of different severity were cellular migration, regulation of responses to various stimuli, cell adhesion and T cell activation for SVD and processes involved in signal transduction, programmed cell death, metabolic processes, collagen catabolism in TVD and these lesions were similar for biological processes such as cell proliferation, differentiation, immune system and apoptosis. Conclusion: This study provides insights into candidate genes, biological processes and pathways involved in CAD and its different severities.