Irreversible Covalent FGFR1-4 Inhibitor
Venetsanakos et al. Page 2668
Many solid tumors demonstrate dysregulation of fibroblast growth factor receptors (FGFRs) but currently no selective inhibitors of FGFR are approved for cancer treatment. Here, Venetsanakos et al. describe the characterization of a pan-FGFR inhibitor PRN1371 that forms a covalent bond with a cysteine in the FGFR active site. The authors describe the high selectivity and strong anti-tumor activity of PRN1371 and further highlight that covalent binding enables PRN1371 to sustain inhibition of FGFR even after the compound is no longer present in circulation. PRN1371 is currently undergoing clinical trials to explore the benefits that these attributes provide to patients with solid tumors.
Death by HDAC Inhibition in Synovial Sarcoma Cells
Laporte et al. Page 2656
Histone deacetylase (HDAC) inhibition in synovial sarcoma has been found to disrupt the driving SS18-SSX protein complex, resulting in apoptosis. To better understand the molecular effects of HDAC inhibitors, Laporte and colleagues used RNA-seq transcriptome analysis to uncover mechanisms of cell death in six human synovial sarcoma cells lines. Specific to SS18-SSX positive cell lines, polycomb-group targets were reactivated resulting in pro-apoptotic transcriptional patterns, which was mediated by ROS activity. Furthermore, HDAC inhibition in a GEM model of synovial sarcoma resulted in significantly decreased tumor burden following treatment with novel HDAC inhibitor quisinostat. This study provides mechanistic support for clinical proposals to use HDAC inhibitors in synovial sarcoma and related diseases.
Sym015 Inhibits MET-driven Tumors
Grandal and Havrylov et al. Page 2780
Increased MET activity is linked to poor prognosis of several human cancers. In this study, Grandal, Havrylov and colleagues present Sym015, an antibody mixture composed of two IgG1 antibodies against non-overlapping epitopes on MET. Synergistic inhibitory activity of the two antibodies comprising Sym015 was demonstrated in vitro and in vivo. Sym015 was found to block ligand binding and downstream signaling and to induce MET degradation. Sym015 also potently induces secondary effector functions. The enhanced effect of Sym015 is predicted to render Sym015 superior to single antibodies targeting MET. Clinical activity of Sym015 is currently being evaluated in a phase I trial.
scTRAIL Fusion Proteins
Hutt et al. Page 2792
TRAIL has been considered as promising anti-cancer therapeutic. Clinical studies with soluble TRAIL, however, were largely disappointing. Here, Hutt and colleagues applied defined oligomerization and tumor targeting to improve the activity of a single-chain version of TRAIL (scTRAIL) and compared three EGFR-targeting as well as two non-targeted hexavalent scTRAIL formats. All EGFR-targeted molecules showed similar and improved activity compared to non-targeted formats in vitro, while in vivo studies highlighted superior efficacy of Fc-comprising molecules. Furthermore, depending on the tumor entity, Fc-scTRAIL may induce equally effective anti-tumor activity as targeted counterparts. This study supports the rational development of potent hexavalent TRAIL-based therapeutics.
- ©2017 American Association for Cancer Research.
Volume 16, Issue 12
