A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2015433118. doi: 10.1073/pnas.2015433118.

Abstract

The CXC chemokine receptor type 4 (CXCR4) receptor and its ligand, CXCL12, are overexpressed in various cancers and mediate tumor progression and hypoxia-mediated resistance to cancer therapy. While CXCR4 antagonists have potential anticancer effects when combined with conventional anticancer drugs, their poor potency against CXCL12/CXCR4 downstream signaling pathways and systemic toxicity had precluded clinical application. Herein, BPRCX807, known as a safe, selective, and potent CXCR4 antagonist, has been designed and experimentally realized. In in vitro and in vivo hepatocellular carcinoma mouse models it can significantly suppress primary tumor growth, prevent distant metastasis/cell migration, reduce angiogenesis, and normalize the immunosuppressive tumor microenvironment by reducing tumor-associated macrophages (TAMs) infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into tumor. Although BPRCX807 treatment alone prolongs overall survival as effectively as both marketed sorafenib and anti-PD-1, it could synergize with either of them in combination therapy to further extend life expectancy and suppress distant metastasis more significantly.

Keywords: CXCR4 receptor; hepatocellular carcinoma; programmed cell death 1; sorafenib; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Diethylnitrosamine / administration & dosage
  • Diethylnitrosamine / toxicity
  • Drug Synergism
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / drug therapy
  • Liver Neoplasms, Experimental / immunology
  • Liver Neoplasms, Experimental / pathology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice
  • Molecular Docking Simulation
  • Rats
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Signal Transduction / drug effects
  • Sorafenib / pharmacology
  • Sorafenib / therapeutic use
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CXCR4 protein, human
  • CXCR4 protein, mouse
  • Receptors, CXCR4
  • Diethylnitrosamine
  • Sorafenib