title: CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?
abstract: Addition of multiple molecularly targeted agents to the existing armamentarium of chemotherapeutics and radiotherapies represents a significant advance in the management of several advanced cancers. In certain tumor types with no efficacious therapy options, these agents have become the first line of therapy, for example, sorafenib in advanced hepatocellular carcinoma or bevacizumab in recurrent glioblastoma. Unfortunately, in many cases, the survival benefits are modest, lasting only weeks to a few months. Moreover, they may not show benefit in patients with localized disease (i.e., in the adjuvant setting). Recent studies have provided increasing evidence that activation of the chemokine CXCL12 (SDF1α) pathway is a potential mechanism of tumor resistance to both conventional therapies and biological agents via multiple complementary actions: (i) by directly promoting cancer cell survival, invasion, and the cancer stem and/or tumor-initiating cell phenotype; (ii) by recruiting "distal stroma" (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor recurrence and metastasis; and (iii) by promoting angiogenesis directly or in a paracrine manner. Here, we discuss recent preclinical and clinical data that support the potential use of anti-CXCL12 agents (e.g., AMD3100, NOX-A12, or CCX2066) as sensitizers to currently available therapies by targeting the CXCL12/CXCR4 and CXCL12/CXCR7 pathways.
authors.affiliation: Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. duda@steele.mgh.harvard.edu
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozin
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Dai
authors.initials: D
authors.lastname: Fukumura
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000627:therapeutic use; D054387:Receptors, CXCR / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C501896:ACKR3 protein, human; D001596:Benzylamines; C540323:CTCE-9908; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D010455:Peptides; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C088327:plerixafor