Abstract C053: NP-G2-044, a novel fascin inhibitor, blocks tumor metastasis and increases antitumor immune response

Abstract

Filopodia are finger-like plasma membrane protrusions that are formed upon remodeling of the actin cytoskeleton beneath the plasma membrane. Fascin protein is the main actin-bundling protein in filopodia and invadopodia which are fundamental to cell shape and motility events. Human fascin expression is low or absent in normal adult epithelial cells but highly expressed in metastatic tumors and in antigen-presenting dendritic cells within the tumor microenvironment. Elevated levels of fascin are correlated with poor prognosis and short survival due to aggressive phenotypes with increased lymph node and distant metastases. Mouse genetic studies demonstrate that deletion of fascin gene delays tumor development, slows tumor growth, reduces metastatic colonization, and increases overall survival. These mouse genetic studies provide strong evidence for fascin’s role in tumor initiation, tumor progression and tumor metastasis, making it an attractive target for drug development. Chemical libraries were screened to identify small-molecule compounds that specifically inhibit the biochemical function of fascin to bundle actin filaments. The inhibitors were optimized to produce the lead compound, NP-G2-044. Preclinical studies showed that fascin inhibitors increase the overall survival of tumor-bearing mice and reinvigorate anti-tumor immune response in syngeneic mouse models of breast, lung, pancreatic and prostate tumors. Fascin protein levels are increased in conventional dendritic cells (cDCs) in the immunosuppressive tumor microenvironment. The number of intra-tumoral activated cDCs is increased following fascin inhibitor treatment. Moreover, together with anti-PD-1 antibody, fascin inhibition markedly increases the number of Ki67+ proliferating and Granzyme-B+ activated CD8+ killer T-cells in tumor tissue. These data demonstrate that fascin inhibitors simultaneously act on tumor cells to block tumor metastasis and on intratumoral DCs to reinvigorate anti-tumor immune response. We are currently conducting a first-in-human phase 1 trial of NP-G2-044 in patients with advanced or metastatic solid tumor malignancies. Citation Format: Vincent Chung, Frank Tsai, Komal Jhaveri, Yufeng Wang, Daniel D Von Hoff, Edward G Garmey, J. Jillian Zhang, Xin-Yun Huang. NP-G2-044, a novel fascin inhibitor, blocks tumor metastasis and increases antitumor immune response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C053. doi:10.1158/1535-7163.TARG-19-C053