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 of new blood vessels from that described the impairment of metastasis in murine breast preexistingblood vessels, can be induced by CXCL12 and cancer models by a neutralizingantibody againstCXCR4 reduced by CXCR4 antagonists (49, 50). However, there are (31). Since then, a large body of supportive work has been also reports that show there is no change in microvessel density done in a variety of in vivo cancer models usingvarious with CXCR4 inhibitor treatment. Strieter et al. proposed that blockade strategies. The CXCR4 antagonist peptide designated some tumor cells have such high levels of CXCR4 expression CTCE-9908 has been used to show that blockingCXCR4 that all the CXCR4 inhibitors would be bound and none may reduces metastasis consistently in eight different murine cancer be left to affect the endothelium which may express much models (32–38). These include i.v. and intracardiac injection lower levels of CXCR4 (51). This phenomenon may be of human breast cancer (34), mouse osteosarcoma, and mouse dependent on the tumor and its stage of development when melanoma cells (32) as models of metastasis; s.c. implantation angiogenesis is required (angiogenic switch). Similarly, some and metastasis from the subcutaneous site of Lewis Lung reports show that some tumors, under normal circumstances or carcinoma (35); orthotopic xenografts of hepatocellular carci- when insulted by current therapies, recruit bone marrow cells noma (37), prostate cancer (33), and breast cancer (34); and such as endothelial progenitor cells (EPC), hemangiocytes/ transgenic model of metastatic breast cancer (38). hematopoietic progenitor cells, and mesenchymal stem cells Similar in vivo observations have been made with CXCR4 (52–56). The main function of EPC and hemangiocytes would blockingsmall molecules, such as AMD3100 (39, 40); peptides, be in vasculogenesis, bringing fresh nourishment to repair such as T22 (41) and TN14003 (42); antibodies (43); and small injured tumor tissue. Also, these cells may secrete growth interferingRNA (22, 40). Administration of AMD3100 factors and cytokines important in the growth of new followinginjection of ovarian tumor cells resulted in reduced vasculature and survival of the tumor. CirculatingEPC have peritoneal metastasis but did not affect survival (39). In a been found to be increased in breast cancer patients by a xenograft model with i.v. injected breast cancer cells, both number of groups, one of which also found an increase in AMD3100 and RNA inhibition by small interferingRNA hematopoietic progenitor cells/hemangiocytes (53, 54). In reduced lungmetastases (40). However, overall survival was murine glioma models, CXCR4 blockade by AMD3100 reduced unaffected (40). When CXCR4 knockdown breast cancer cells recruitment of EPC to vasculogenic gliomas (57). (by RNA inhibition) were orthotopically implanted, all mice Treatment of mice and cancer patients with taxanes, such as survived without metastatic lesions in contrast to control paclitaxel, but not other chemotherapies, such as gemcitabine, animals that all died from metastatic disease (40). I.v. injection mobilized EPC at least in part by secretion of CXCL12 (58). of melanoma cells generates tumor masses in the lungs that Pretreatment with a VEGFR-2 blockingantibody prevented the were inhibited by T22 (41). The analogue to T22 designated mobilization. Blockage of recruitment of EPC by a CXCR4 TN14003 suppressed primary tumor growth by inhibiting antagonist may also be effective and may lead to reduced tumor tumor angiogenesis and prevented lung metastasis in an viability. The CXCR4 antagonist CTCE-9908 has been success- orthotopic head and neck cancer model (42). By usingthe fully used in combination with docetaxel in murine prostate same tumor cells in an i.v. model, TN14003 treatment reduced cancer and breast cancer models. In the prostate cancer model, the number of lungmetastases (42). Injection of prostate a proportion of the mice became free of primary tumor and cancer cells into the left cardiac ventricle resulted in osseous metastases, although it continued to grow in cases in which the metastases that can be reduced by an anti-CXCR4 antibody primary was not eradicated (36). In the breast cancer model, an (43). Similarly, the growth of prostate cancer cells that were additive effect was observed both in reducingthe growthof the injected into the tibia was reduced by a CXCR4 blocking primary tumor and in inhibitinglungmetastases (38). antibody (43). Approximately 40% of hepatocellular carcinoma patients are CXCR4 activation not only induces a panel of cytoskeletal routinely treated with transarterial chemoembolization as first- changes leading to cell migration (as discussed in the previous line therapy in which chemotherapy is administered directly to section) but also induces the production of matrix metal- the tumor followed by vessel occlusion. It was observed that the loproteinases at the primary tumor site (14). This is important tumor responds by recruitingEPC and hemangiocytesfor for detachment from the tumor and migration through the support, leadingto tumor recurrence (56). This recruitment extracellular matrix into the circulation. Upon arrival in an seems to involve CXCL12/CXCR4. The use of CXCR4 antago- organ high in CXCL12, interaction of CXCR4 with CXCL12 nist CTCE-9908 in combination with hepatic ligation, compa- activates integrins on the tumor cells, allowing them to adhere rable with transarterial chemoembolization in a rat model, to endothelial cells and subsequently migrate across the controlled tumor growth by reducing the recruitment of these

www.aacrjournals.org 7977 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 bone marrow cells, decreasingblood vessel density in the models (36, 38, 56). A phase I/II clinical trial is completed and tumor, and causingthe tumor to become necrotic. The overall final results have been reported (65). Adverse events such as survival of rats was significantly increased (56). phlebitis are mild. More importantly, early signs of efficacy In glioblastoma patients, the escape of the tumor from anti- have been observed in the form of patients with stable disease. VEGF therapy correlated with an increase in plasma CXCL12 A phase II clinical trial in hepatocellular carcinoma with the use (59). This represents a promisingopportunity to use a CXCR4 of CTCE-9908 in combination with transarterial chemoembo- antagonist in combination with an anti-VEGF agent. CXCL12 lization is beinginitiated. The hypothesis is that CTCE-9908 and VEGF also work synergistically in ovarian cancer (60). In would block the recruitment of bone marrow–derived support the case of breast cancer, HER2-positive tumor cells exhibit cells by the tumor after the transarterial chemoembolization increased expression of CXCR4. This is related to inhibition of procedure in addition to blockingthe metastatic process. receptor degradation through the ubiquitin pathway (61). Primary tumor response, effects on disease progression, and Moreover, CXCL12/CXCR4 seems to transactivate HER2 in survival are anticipated. breast cancer and prostate cancer (62, 63). It may be postulated On the hematologic malignancy side, AMD3100 (Genzyme that a CXCR4 antagonist can be used in combination with Corp) is currently beingtested in a phase I/II trial in therapies targeting VEGF and HER2. Indeed, CXCR4 antagonist combination with mitoxantrone, etoposide, and cytarabine as CTCE-9908 has been recently used in combination with the listed in clinicaltrials.gov.1 The investigators hypothesized that VEGFR2 blockingantibody DC101 in a breast cancer model. the bone marrow stroma interacts with AML blasts through The results showed a further inhibition of the primary tumor CXCL12/CXCR4 to produce chemoresistance. Disruption of and lungmetastases comparingthe combination therapy with this interaction would sensitize the acute myelogenous either therapy alone (38). leukemia blasts to the cytotoxic effect of chemotherapy. A It is clear that there is more to CXCR4 antagonists than just number of preclinical animal studies have shown this effect in antimetastasis. The best strategy for their use may be in hematologic malignancies (66). A similar observation was combination with other targeted therapies or standards of care reported with the CXCR4 antagonist peptide RCP168, an that induce CXCL12 secretion or migration of CXCR4+ cells, analogue of the viral macrophage inflammatory protein II, whether bone marrow–derived cells or tumor cells. The design although no clinical studies are reported (45). Another CXCR4 of a clinical trial to examine strictly antimetastatic effects may antagonist has recently entered clinical trials. MSX-122 is an involve surgery and chemotherapy to treat the primary tumor orally available small molecule produced by Metastatix, Inc. A and current metastases. A CXCR4 antagonist given in a phase I trial was reported as suspended on clinicaltrials.gov on consolidation settingmay inhibit any future metastases (64). June 30, 2008.2 There is a report that this compound inhibits However, this would probably require a protracted clinical trial the growth of primary tumor and synergizes with paclitaxel in to prove sufficient evidence of efficacy. Moreover, a regulatory an orthotopic model with human lungadenocarcinoma (67). A approvable end point for inhibition of metastasis has not been number of other compounds show activity in the preclinical recognized. Time to progression, tumor response, and similar stage, some showing efficacy in mouse cancer models whereas end points are not appropriate to measure changes in the others are targeting other diseases and disorders. These include amount or rate of metastasis. Further work with regulatory CXCR4 antagonist AMD3465 and AMD070 (Genzyme Corp), agencies is needed to identify end points suitable to quantify as well as T22, T140, FC131, and other derivatives (Biokine disease burden in the context of metastasis and its ultimate Therapeutics, Ltd., and Kyoto University). effect on overall survival. Conclusion Translational Approaches toward Clinical Studies It is clear that CXCR4 blockade for oncology is moving from A leadingCXCR4 antagonistfor solid tumors is CTCE-9908 preclinical research into the clinical. A number of challenges (Chemokine Therapeutics Corp). This compound is derived remain, includinga method to screen for patients and tumor from the amino acid sequence of the NH2 terminus of human types likely to respond, biomarkers as indicators of efficacy, the CXCL12. Preclinical efficacy studies were done in eight appropriate stage of disease to treat, regulatory approvable end metastatic models as discussed in the previous section points, and appropriate combinations with current and future (32–38). Throughout, CTCE-9908 showed a consistent anti- therapies. Marketingapplications for AMD3100 in the setting metastatic effect whether tumor cells were injected (i.v., of stem cell mobilization and transplantation have been intracardiac), implanted (s.c., orthotopic), or spontaneously submitted to the Food and DrugAdministration and European developed in a transgenic model. In the breast cancer models, it Union. The future is bright for CXCR4 antagonists as a was observed to reduce the growth of the primary tumor by therapeutic approach for the management of cancer. 40% to 80% (34, 38). Recently, reduction of primary tumor growth or shrinkage of primary tumor has been reported in combination with various treatments, such as chemotherapy, Disclosure of Potential Conflicts of Interest anti-VEGF therapy, and hepatic artery ligation in mouse and rat D.Wong, W. Korz: employees and ownership interest: ChemokineTherapeutics Corporation.

1http://www.clinicaltrials.gov/ct2/show/NCT00512252?term=amd3100&rank=3. Acknowledgments Accessed June 30, 2008. 2 http://www.clinicaltrials.gov/ct2/show/NCT00591682?term=msx-122&rank=1. We thank Dr. Frances Balkwill for her review of the manuscript and insightful Accessed June 30, 2008. suggestions.

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Donald Wong and Walter Korz

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