Blocking Chemokines and or Chemokine Receptors as Approaches to Cancer Therapy

Targeting specific chemokines derived from tumors that may affect tumor angiogenesis are a promising area for the future. Antibodies to neutralize CXCL5 and CXCL8 reduced tumor growth, vascularity, and metastasis in experimental models of nonsmall-cell lung cancer (Arenberg et al., 1998, 1996). Neutralizing antibodies to CCL20 inhibited the growth of prostate cancer cells that overexpress CXCR4 in a tumor xenograft model (Beider et al., 2009).

Higher expression levels of selected chemokine receptors have been reported in many cancer cells compared to their normal counterparts. A partial list includes, for breast (CXCR3, CXCR4, CCR7, CXCR7, CCR5),ovarian (CXCR4), prostate (CXCR4, CXCR5, CCR9, CCR5, CX3CR1), pancreas (CXCR4, CXCR1/2, CCR6), bladder (CXCR4), colon (CXCR3, CXCR4, CCR6, CCR7, CXCR1/2), stomach (CCR7), and thyroid (CXCR4) (Wu, Lee, Chevalier, & Hwang, 2009). It appears that three receptors, CCR7, CXCR4, and CXCR7, are prominently expressed in cancer and more specifically in metastasis (Meijer, Ogink, & Roos, 2008; Zlotnik, 2006). Preclinical data suggest that inhibition of CXCR4 by neutralizing antibodies, siRNA against CXCR4, and antagonists such as AMD3100, MSX-122, or CTCE-9908, inhibit growth and reduce metastasis (Kim et al., 2008; Liang et al., 2004; Slettenaar & Wilson, 2006; Yoon et al., 2007). Another peptide-based CXCR4 receptor antagonist, TN14003, inhibited primary tumor growth and metastasis of head and neck cancer

TABLE I Chemokine Receptor Antagonists Currently in Clinical Trials for Treatment of Cancer

Target

Compound, company

Development status

Disease

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