VERU-111 as a promising therapeutic for colorectal cancer 2419

Abstract Description The rising incidence of colorectal cancer (CRC) in recent decades has ranked it as the third most common cancer and second most common cause of cancer-related mortality globally. Despite having available treatments, developing new therapies remains essential as the existing therapies are limited by resistance and/or off-target toxicity. We observed that VERU-111, a potent orally available tubulin inhibitor in vitro halts the wound healing in HCT-116 and DLD-1 cell lines and arrests the cell cycle in the G2/M phase. Next, we assessed the efficacy of VERU-111 in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced in vivo model of CRC. Oral administration of VERU-111 reduced tumor burden and increased colon length. There was a significant increase of CD8+CXCR3+ effector T cells and natural killer T (NKT) cells in the colon tumor microenvironment (CTM) in the VERU-111 group as compared to the AOM/DSS. Intriguingly, VERU-111 treatment reduced systemic and CTM macrophage infiltration as well as reduced the frequency of myeloid and dendritic cells (DCs) expressing PD-L1. We also noticed induction of apoptosis in tumors of VERU-111 treated mice, as evidenced by upregulation of apoptotic markers BAX and cleaved caspase-3. These findings suggest that VERU-111 effectively reduces tumor burden, induces effector T cells and apoptosis, as well as modulates myeloid cells expressing PD-L1 for suppression of CRC and offers promising insights to explore it further as a therapy for CRC. Funding Sources This study was supported by grant from NIH (NIAID R01 AI140405) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)