CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers.
Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
Burger
J A
JA
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1402, USA.
Peled
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019718:Receptors, CXCR4