Amelioration of Tumor-Promoting Microenvironment via Vascular Remodeling and CAF Suppression using E7130: Biomarker Analysis by Multi-modal Imaging Modalities.

E7130 is a novel anti-cancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAFs) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry (cytometry by time-of-flight [CyTOF]) analysis, multiplex-immunohistochemical (IHC) analysis, and magnetic resonance imaging (MRI). Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGF-β1 production, a precursor of TGF-β1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGF-β1 in plasma. To our best knowledge this is the first report to show a reduction of TGF-β1 production in TME. Furthermore, Multiplex-IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a non-invasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.