At the Bedside: Profiling and treating patients with CXCR4-expressing cancers

Abstract

The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization).However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, Bio-LineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach.The current status and future directions for radioimaging and treating patients with CXCR4expressing hematologic and solid malignancies are reviewed. See related review -At the Bench:

Recent Advances in CXCL12/CXCR4 Antagonists and Nano-Based Drug Delivery Systems for Cancer Therapy

“…Unlike other chemokine receptors, CXCR4 regulates inflammatory and immune processes by primarily acting on leukocytes [ 2 ]. CXCR4 is expressed in a variety of cell types, including lymphocytes, hematopoietic stem cells, endothelial cells, epithelial cells, stromal fibroblasts, and cancer cells; the expression of CXCR4 is upregulated under conditions of hypoxia, stress, and injury [ 9 , 10 , 11 ].…”

Colorectal Cancer: The Contribution of CXCL12 and Its Receptors CXCR4 and CXCR7

“…However, more recently, the approval of targeted therapies with EGFR or VEGF antibodies has importantly improved the overall survival, approaching 30 months in clinical trials [ 262 ], but the relative unavailability of biomarkers in metastatic CRC has slowed the progress in tumor curacy. Because of the bad prognostic value of CXCR4 overexpression across different tumors, CXCR4-inhibition-based therapies have been therapeutically evaluated in hematologic and solid malignancies, either as monotherapy or in combination with chemotherapies or immunotherapies (for review, see [ 263 , 264 , 265 ]). Among the drugs tested in clinical trials, CXCR4 small molecule antagonists, fully humanized anti-CXCR4 antibodies and CXCR4 or CXCL12 peptide inhibitors represent the most advanced programs of CXCR4 inhibition in solid tumors.…”

In Vivo Targeting of CXCR4—New Horizons

“…Although many underlying mechanisms and their implications for disease progression are not elucidated yet, most tumors import a worsening prognosis with increasing CXCR4 expression, which is known to play an important role in both tumor cell proliferation and metastasis [5]. Non-invasive imaging of receptor expression has become feasible through the introduction of radiolabeled ligands that allow for whole-body SPECT or PET [2], with the theranostic concept based on the cyclic pentapeptide tracers [ 68 Ga]Pentixafor and [ 177 Lu]Pentixather being the farthest advanced into clinical practice.…”