Science

X-Ray Crystal Structure of Fascin

The co-founders of Novita solved the X-ray crystal structure of fascin and identified the actin-binding sites, which allowed for the screening, modification and optimization of small molecule fascin inhibitors.

Links: Chen et 2010, Yang et al 2013

Tumor Cell Migration

Tumor cell migration requires dynamic rearrangements of the actin filament network to form finger-like protrusions called filopodia. Metastatic tumor cells are rich in filopodia, and the numbers of filopodia correlate with a cell’s invasiveness. Fascin is the primary protein responsible for cross-linking actin filaments in filopodia. Elevated levels of fascin have been found in many types of metastatic tumors.

Role of Fascin in Metastasis

Tumor metastasis is the major cause of mortality in cancer patients. Tumor cell migration and invasion are critical steps in metastasis. Migration provides tumor cells the ability to leave the primary tumor (local invasion), enter the blood vessels (intravasation), and then exit the circulation and infiltrate distant tissues/organs (extravasation). It is critical to understand and interrupt the process of tumor metastasis as that is ultimately the terminal event for most cancer morbidity and progression to mortality.

Role of Fascin in Tumor Immune Response

Fascin inhibition, particularly in combination with PD-1/PD-L1 checkpoint inhibition, is associated with increased levels of activated dendritic cells, increased antigen uptake by these dendritic cells, and increased levels of activated cytotoxic killer T-lymphocytes in the tumor microenvironment (TME).

Fascin gene expression

High levels of fascin are expressed during embryonic stages
In adults, fascin is present only in microglial cells, microcapillary endothelial cells and dendritic cells
Mice lacking the fascin gene in its genome (fascin-/-mice) developed normally
Patients with many types of tumor show fascin gene gain or amplification (> 3 copies of the gene)

The Novel Fascin Inhibitor NP-G2-044

NP-G2-044 is a small molecule that inhibits the function of fascin, leading to the decrease of tumor growth, the block of tumor metastasis, and the enhanced anti-cancer immune response. NP-G2-044 acts by inhibiting the actin-bundling function of fascin, with inhibitory capabilities at low nanomolar concentrations in vitro. Specificity against the activity of fascin has been observed.