Translating an Antagonist of Chemokine Receptor CXCR4: from Bench to Bedside Donald Wong and Walter Korz
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Molecular Pathways Translating an Antagonist of Chemokine Receptor CXCR4: From Bench to Bedside Donald Wong and Walter Korz Abstract The majority of current cancer therapies focus on a primary tumor approach. However, it is metastases that cause the majority of cancer deaths. The metastatic process has been shown repeatedly to be greatly influenced by chemokines such as CXCL12 [stromal cell derived factor-1 (SDF-1)] and its receptor CXCR4. The activation of this pathway has been reported to modulate cell migration, survival, proliferation, and gene transcription through G proteins, phosphoinositide-3 kinase, Akt, extracellular signal-regulated kinase, arrestin, and Janus- activated kinase/signal transducers and activators of transcription. A wide variety of strategies, such as peptides, small molecules, antibodies, and small interfering RNA, have been used to target this pathway. Treatments in combination with current therapies seem to be especially promising in preclinical studies. A few compounds are advancing into early stages of clinical development. In this article, we will review the development of CXCR4 antagonists in oncology. Background fortuitous circumstance for translational research. This pathway is critical especially duringearly development, in the processes Metastasis is a complex process that can be driven by hypoxia of hematopoiesis, organogenesis, and vascularization (4–6). and insults to the tumor, such as chemotherapy. It is the Gene knockout is lethal in mice. In humans, heterozygous metastatic process that accounts for >90% of cancer-related mutations in the CXCR4 gene lead to the development of the deaths. To date, most therapeutic approaches focus on warts, hypogammaglobulinemia, infections, and myelokathexis techniques that affect the primary tumor. There is currently syndrome (7). The CXCL12/CXCR4 pathway has also been co- no drugapproved that specifically targetsthe metastatic opted by cancer cells in the processes of metastasis, growth, and process. It has been longknown that different types of cancer survival. preferentially metastasize to specific organs. Recent reports show that pivotal to this phenomenon is the production of The CXCL12/CXCR4 Signal Transduction Pathway chemokines by the organs to which the tumor cells metastasize. CXCL12 is the sole ligand for the chemokine receptor CXCR4. One of the major chemokine receptors that is expressed by This receptor has been described as undergoing dimerization cancer is CXCR4, the receptor for CXCL12 [stromal cell derived after bindingto CXCL12 or alternately in its unbound factor-1 (SDF-1)]. configuration. The dimer state seems to be important to activate The CXCL12/CXCR4 pathway has been widely studied. signal transduction pathways (8, 9). Upon binding of CXCL12 CXCR4 is a 352-amino-acid, seven-transmembrane G-protein to CXCR4, the receptor is stabilized into a conformation that coupled receptor. CXCL12 is its sole ligand (1). The two most activates the heterotrimeric G-protein, Gi beinga major investigated isoforms of CXCL12 are CXCL12a and CXCL12h, component (refs. 9, 10; Fig. 1). However, other G-protein the latter havingfour additional amino acids at the COOH subtypes and non–G-protein-mediated pathways are also used. terminus compared with the former. Four additional isoforms Gia and Ghg both dissociate from the receptor and regulate a (CXCL12g, CXCL12y, CXCL12q, and CXCL12f) were recently wide variety of downstream pathways, includingactivation of described, each with different number of amino acid extensions phospholipase C, phosphoinositide-3 kinase, and inactivation compared with CXCL12a (2). There is remarkable homology of adenylyl cyclase. Signaling through the phosphoinositide-3 between CXCL12a expressed by human and mice with only a kinase pathway leads to the activation of PAK and cell single conservative change in amino acids (3). This is perhaps a polarization, the first step in migration. Phosphoinositide-3 kinase and various tyrosine kinases that activate Akt and Cdc42 are involved in actin polymerization. Phospholipase C–mediated events, such as calcium release and protein kinase C activation, as well as focal adhesion kinase, pyk2, paxillin, and Authors’ Affiliation: Chemokine Therapeutics Corporation, Vancouver, British extracellular signal-regulated kinase are important in the Columbia, Canada adhesion process, leading to cell migration (refs. 11–14; Fig. 1). Received 5/20/08; revised 7/7/08; accepted 7/9/08. In parallel, activation of Akt, extracellular signal-regulated Requests for reprints: Donald Wong, Chemokine Therapeutics Corporation, kinase, and tyrosine kinases such as Src leads to transcription of Suite 400, 1727 West Broadway,Vancouver, British Columbia, Canada V6J 4S5. E-mail: [email protected]. genes involved in migration (13, 14). Whether CXCR4 is F 2008 American Association for Cancer Research. involved in the survival and proliferation of tumor cells doi:10.1158/1078-0432.CCR-07-4846 remains controversial, perhaps because this may be tumor www.aacrjournals.org 7975 Clin Cancer Res 2008;14(24) December 15, 2008 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2008 American Association for Cancer Research. Molecular Pathways dependent. The activation of extracellular signal-regulated arrestin also elicits signals through various mitogen-activated kinase and Akt can both potentially contribute to the survival protein kinases and modulates various signal pathways (18). and growth of tumor cells (refs. 15, 16; Fig. 1). Migration, Stimulation of other G-protein coupled receptors may also survival, and growth are all components of the metastatic down-regulate CXCR4 signaling through a process called process. heterologous desensitization (19). Traditionally, it is believed that the Janus-activated kinase/ A recent report described a number of CXCR4 isoforms and signal transducers and activators of transcription (JAK/STAT) mutant CXCR4 receptors. They vary in levels of glycosylation pathway is activated through CXCR4, partially independent of and functionality (20). Thus, although CXCR4 is expressed, it G-protein. The association of JAK with CXCR4 activates STAT may differ structurally and functionally in different cells. It is proteins, which translocate to the nucleus and regulate not completely surprisingthat CXCR4+ neuroblastoma cells transcription (9). However, a recent report that used genetically that do not undergo chemotaxis toward bone marrow–derived modified cells rather than inhibitors raised questions about this CXCL12 have been isolated (21). However, it remains a activity (17). It remains unclear whether CXCL12 bindingto possibility that the primary tumor from which these cells were CXCR4 in patients with tumors activates the JAK/STAT derived remains responsive to CXCL12 and these cells pathway. This perhaps reflects the differences amongcell lines, subsequently became desensitized. Similarly, a panel of breast normal cells, and primary tumor cells as Moriguchi et al. cancer cells that all express CXCR4 uniformly exhibit different suggested (17). metastatic potentials in mice (10). Only the highly invasive Down-regulation of the CXCR4 receptor is initiated by cells show signal transduction, actin polymerization, and phosphorylation of its cytoplasmic tail. Subsequent to the chemotaxis subsequent to CXCL12 exposure. The reason is bindingof arrestin to the COOH terminus of CXCR4, the partly related to the inability of the G-protein subunits to form receptor is internalized through endocytosis (Fig. 1). Degrada- an ahg heterotrimeric complex with CXCR4 in nonmetastatic tion of CXCR4 occurs in the lysosome. However, bindingof lines. This also suggests that screening potential patients for Fig. 1. Signal transduction pathway induced by CXCL12 binding to receptor CXCR4. Downstream actions mainly related to migration and chemotaxis. Other effects include survival, proliferation, and transcription. Current inhibitors of this pathway are peptides, small molecules, and antibodies that inhibit ligand/receptor binding. ClinCancerRes2008;14(24)December15,2008 7976 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2008 American Association for Cancer Research. CXCR4 Antagonist for Cancer Therapy clinical trials by simply assessingCXCR4 expression may be endothelium into the organ to form metastases (22, 44). The misleading. regulation of these processes may affect their role in metastasis of individual tumors. Clinical-Translational Advances Other less studied CXCR4-related effects are survival, proliferation, angiogenesis, and vasculogenesis. CXCL12 pro- It was reported in 2004 that 23 types of cancers express duced by stromal cells may induce a survival or antiapoptotic CXCR4 (22). This number continues to grow. Prominent signal in tumors that reduce their susceptibility to current CXCR4+ tumors include breast cancer (23), ovarian cancer treatments such as chemotherapy (45, 46). This is similar to (24), prostate cancer (25), hepatocellular carcinoma (26), and usurpingthe role CXCL12 usually plays in hematopoiesis in the hematologic malignancies (27). The expression of CXCR4 is bone marrow when tumor cells metastasize to the bone (14). regulated in many tumors by hypoxia and cytokines such as CXCR4 antagonists also reduced tumor growth in several VEGF and TNF (28–30). The classic article linkingCXCR4/ murine models (47, 48). It has been shown in some studies CXCL12 to metastasis in vivo is the article by Mu¨ ller et al. that angiogenesis, the growth