Although it is suggested in the art i) that the blockage of CXCR7 employed along with CXCR4 blockage may be useful for the treatment of SDF-1-dependent tumor progression and metastasis (R B Maksym et al., 2009, The role of stromal-derived factor-1-CXCR7 axis in development of cancer, European Journal of Pharmacology, 625 (1-3), pages 31-40) and ii) that some small molecular inhibitors, such as CCX733 or CCX266, siRNA and blocking antibodies (clones Mab 11G8, Mab 9C4 see e.g., US20070167443; clone 358426 (R&D Systems); Mab 8F11 (Biolegend)), may be useful for therapeutic interference with CXCR4-mediated activation of integrins (T N Hartmann et al., 2008, A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells, Journal of Leukocyte Biology, 84, pages 11301140), the biology of CXCR7 is still poorly understood as the mechanism(s) of action through which CXCR7 acts is unclear because i) it may act as a kind of decoy or signalling receptor depending on cell type—R M Maksym et al., supra and since ii) the interplay between I-TAC and SDF-1 binding to CXCR7 is unclear.
The identification of selective therapeutically effective anti-CXCR7 agents is not only challenging because of its poorly understood biology (such as e.g., mechanism of action, e.g., of the potential agonists CCX733 or CCX266 versus antagonists, interplay with CXCR4, recognition of important epitopes, cross-reactivity of the compounds CCX733 or CCX266 and associated toxicity), it is also acknowledged in the art (see e.g., Naunyn-Schmied Archives Pharmacology 379: 385-388) that the generation of an anti-GPCR therapeutic agent such as an anti-CXCR7 agent is difficult since i) the native conformation of active CXCR7 in cancer cells is not exactly known, and ii) it is expected that CXCR7 shows low immunogenicity (due to a limited number of extracellular surface exposed amino acid residues that are in addition very conserved, e.g., mouse-human CXCR7 is 96% homologous).
Furthermore, compounds (CCX733, CCX754), which can selectively block binding of CXCL11 and CXCL12 to CXCR7, function like chemokine ligands with respect to homodimerization, i.e., they enhance CXCR7 homodimerization by 2.5 to 3.5 fold with significant increases (P<0.05) first detected at 10 and 100 nM (K E Luker et al., 2009, Imaging chemokine receptor dimerization with firefly luciferase complementation, FASEB journal, 23, pages 823-834).
CXCR7 has been attributed a potential role in tumour development because its expression provides cells with a growth and survival advantage. It was recently demonstrated that CXCR7 promotes the growth of breast and lung tumours and enhances lung metastases (Proc. Natl. Acad. Sci. USA 2007 104:15735-15740). Moreover, CXCR7 expression is correlated with tumour aggressiveness in prostate cancer (J. Biol. Chem. 2008 283:4283-4294). Administration of a small molecule antagonist to CXCR7 resulted in impediment of tumour growth in animal models, validating CXCR7 as target for development of novel cancer therapeutics (J. Exp. Med. 2006 203:2201-2213).
Head and neck cancers are among the most prevalent tumors in the world. Despite advances in the treatment of head and neck tumors, the survival of patients with these cancers has not markedly improved over the past several decades because of the inability to control and poor understanding of the regional and distant spread of this disease. Head and neck cancers consistently rank among the six most frequently diagnosed cancers in the world. Cancers of the oral cavity and pharynx alone account for some 300,000 new cases worldwide and little under 200,000 deaths annually. Over 90% of head and neck cancers are squamous cell carcinomas of the upper aerodigestive tract, including the oral cavity, pharynx, larynx, and paranasal sinuses. In addition, epithelial head and neck tumors can arise in the salivary and thyroid glands. Despite advances in our understanding and advances in the prevention and treatment of head and neck cancers, the survival of patients with head and neck cancers has not significantly improved over the past several decades.
USPTO Backgrounds
USPTO Backgrounds