Abstract
Fascin is an actin-bundling protein that is critical for filopodial formation and other cellular cytoskeletal structures. An elevated expression of fascin has been observed in tumor cells and is correlated with a shorter survival of cancer patients. Given its roles in tumor cell migration and invasion, we have developed small-molecule fascin inhibitors to prevent and delay tumor metastasis. Here we report the characterization of a new fascin inhibitor in mice. In addition to its inhibitory effects on tumor metastasis, we also report that fascin inhibitors can decrease the growth of specific subtypes of cancers, including epidermal growth factor receptor (EGFR)-high triple-negative breast cancer, and activated B-cell subtypes of diffuse large B-cell lymphoma. Hence, fascin inhibitors can be used to not only inhibit tumor metastasis, but also decrease the tumor growth of specific cancer types.
Highlights
Fascin is the main actin cross-linker in filopodia and shows no amino acid sequence homology with other actin-binding proteins [1,2,3,4,5]
We reveal that NP-G2-044 decreases the cell proliferation and primary tumor growth of activated B-cell diffuse large B-cell lymphoma, diffuse mixed lineage lymphoma, and epidermal growth factor receptor (EGFR)-high triple-negative breast cancer
To facilitate efficacy studies of fascin inhibitors in animals, we first carried out pharmacokinetic (PK) studies of a fascin inhibitor, NP-G2-044, in mice (Figure 1A)
Summary
Fascin is the main actin cross-linker in filopodia and shows no amino acid sequence homology with other actin-binding proteins [1,2,3,4,5]. Studies using cancer patient biopsies demonstrate that fascin is a biomarker of metastases [6,7,8,9,10]. Elevated fascin mRNA and/or protein levels are found in almost all types of metastatic tumors, and are correlated with clinically aggressive phenotypes, a poor prognosis, and shorter survival [11,12]. Human fascin expression is low or absent in normal adult epithelial cells, but highly expressed in metastatic tumors [13,14]. Fascin gene-knockout mice were normal, likely due to the functional compensation of other actin-bundling proteins during embryonic development [15]. A deletion of the fascin gene delayed tumor development, slowed tumor growth, reduced metastatic colonization, and increased the overall survival in a spontaneous mouse model of pancreatic cancer [16]
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