Use of modulators of CCR5 in the treatment of cancer and cancer metastasis

#This disclosure is directed, in part, to a method of determining whether a subject having cancer is at risk for developing metastasis of the cancer and a method of blocking cancer methastasis.

#Breast cancer causes the death of 40,000 women in the USA and 410,000 women in the world annually.1 Despite advances in the treatment of the disease, 20% to 30% of patients with early breast cancers will experience relapse with distant metastatic disease.2 In those patients, metastasis is the main cause of death. Patients with basal tumors have increased risk of metastasis and lower survival rate.3,4 Kennecke et al. studied 3,726 breast cancer patients and reported that the basal tumors have higher frequencies of metastases and reduced time from identification of metastases to death compared to that of patients with luminal A or B tumors.4 The absence of AR, ER, and HER-2 commonly found in basal breast tumors5 means that they are unlikely to respond to hormone therapies or HER-2 targeted therapies. Currently, chemotherapy, radiation, and surgery are the only choices for patients with basal breast cancers, but all demonstrate poor outcomes.6 The need for a specific targeted therapy for basal breast cancer remains urgent.

#Certain aspects of embodiments disclosed herein by way of example are summarized below. It should be understood that these aspects are presented merely to provide the reader with a brief summary of certain forms an invention disclosed and/or claimed herein might take and that these aspects are not intended to limit the scope of any invention disclosed and/or claimed herein. Indeed, any invention disclosed and/or claimed herein may encompass a variety of aspects that may not be set forth below.

#The foregoing summary, as well as other features, aspects, and advantages of the present invention and the following detailed description of embodiments of the invention, will be better understood when read in conjunction with the claims and the appended drawings of an exemplary embodiments, wherein:

#FIG. 1A illustrates a heatmap of the expression of CCL5 and its receptor CCR5 in samples from patients with breast cancer divided by molecular subtype (luminal A, luminal B, basal, normal-like, and Her-2) based on their gene expression pattern;

#FIG. 1B includes plots 1B1 through 1B5, which illustrates scatter plots and correlation analysis (Student t test) of the expression of CCL5 and CCR5 among the breast cancer molecular subtypes of luminal A, luminal B, basal, normal-like, and Her-2;

#Chemokine (C-C motif) ligand 5 (“CCL5”), also known as RANTES (an acronym for Regulated on Activation, Normal T cell Expressed and Secreted) is a protein which in humans is encoded by the CCL5 gene. Its receptor, C-C chemokine receptor type 5 (“CCR5” or “CD195”) is a protein found on the white blood cells. CCR5 is the main coreceptor used by macrophage (M)-tropic strains of human immunodeficiency virus type 1 (HIV-1) and HIV-2, which are responsible for viral transmission. CCR5 therefore plays an essential role in HIV pathogenesis. A number of inflammatory CC-chemokines, including MIP-1 alpha, MIP-1 beta, RANTES, MCP-2, and HCC-1[9-74] act as CCR5 agonists, while MCP-3 is a natural antagonist of the receptor. CCR5 is mainly expressed in memory T-cells, macrophages, and immature dendritic cells, and is upregulated by proinflammatory cytokines.

#Classes of antiretroviral medications with activity against HIV include nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, and CCR5 receptor antagonists. CCR5 antagonists exert their antiviral activity against HIV by blocking entry of CCR5-tropic viruses into the CD4 T cell. As a result, CCR5 antagonists have historically only been associated with expression in inflammatory cells in the immune system.

#Prior to the present disclosure, the roles of the chemokine CCL5 and its receptor CCR5 in cancer progression were unclear. As disclosed herein, patients with cancers expressing CCL5 and its receptor CCR5, present new drug targets. As disclosed herein, treating cancers that expressed CCL5 and its receptor CCR5 with drugs that blocking their activities respecting CCL5 and its receptor CCR5 selectively affect these cancer cells that express mutant chemokine CCL5 and its receptor CCR5. In one embodiment, a subpopulation of human breast cancer cell lines were found to express CCR5 displayed a functional response to CCL5.