Prostate cancer is the major cause of cancer-related morbidity and mortality in United States Veterans;it ranks above that found among general population. Although, prostate cancer can be effectively managed if diagnosed early when the disease is confined to prostate, effective cure is limited in advanced disease when the cancer has spread to extra-prostatic tissues. Current research has shown two main pathways of prostate growth that are deregulated in cancer, the one is androgen-androgen receptor regulated growth and the other peptide hormones, such as Epidermal Growth Factor (EGF) and Insulin-like growth factor-1, stimulated prostate tumor growth and survival. However, in this proposal it is proposed that there is a third pathway of tumor growth stimulated by the activities of cytokines and chemokines and their receptors. Further, it is hypothesized that a Chemokine receptor (CXC Receptor 7 or CXCR7) regulates prostate tumor cell growth by coupling with the EGF Receptor, EGFR in a potentially ligand-independent mechanism. Unraveling the mechanism of CXCR7- EGFR interaction that leads to tumor cell growth, invasion and metastasis is the main objective of proposed work.
Three specific aims are proposed to achieve stated objective.
Specific Aim 1 is to determine the molecular mechanism of CXCR7 and EGFR interaction that leads to mitogenic activation of non-malignant and/or malignant prostate cells. The proposed work is based on the hypothesis that that over-expression of CXCR7 leads to increase in cell growth in normal and malignant cells via constitutive physical interaction with EGFR in plasma membrane and subsequent activation of EGFR-mediated mitogenic signaling. The hypothesis will be tested, by analyzing the interacting domains of CXCR7 and EGFR, using in vitro site-directed mutagenesis, chemical-cross linking, co-immunoprecipitation, confocal microscopy and time- resolved fluorescence microscopy.
Specific Aim 2 is to determine the role of CXCR7 in tumor cell motility, invasion and enhancement of angiogenic potential of CRPC cells and determine whether its interaction with EGFR is needed for one or more of this function, and Specific Aim 3 is to investigate the role of CXCR7 in CRPC bone metastasis and the therapeutic potential of inhibiting CXCR7 in local and metastatic growth using small molecule-inhibitors of site-specific phosphorylation and mitogenic signaling domains. It is anticipated that the proposed research will be able to provide mechanistic understanding of the Chemokine receptor controlled prostate cancer growth by heterotypic interaction between CXCR7 and EGFR and suggest potential therapeutic avenue to compromise this pro-tumorigenic nexus.
Prostate cancer is the disease of the elderly, affecting about 1 in 6 men over the age of 60, and 50% of all men at sub-clinical level. The prevalence of prostate cancer in American Veterans is the highest among all other groups. The treatment of veterans with prostate cancer is not different from that offered to general population. The present proposal seeks to identify novel therapeutic target, a multi-chemokine receptor called CXCR7, expressed in advanced prostate cancers, and specifically elevated by hormone therapy. Since patients who face the recurrent prostate cancer are commonly treated with hormone therapy (androgen deprivation) CXCR7 level may be up- regulated in such patients, therefore, such patients are likely to benefit by suppressing CXCR7. The experiments proposed tests the efficacy of inhibitors of CXCR7. A possible outcome of this research is the emergence of new drug for hormone refractory prostate cancer. Therefore, the present proposal is highly relevant to VA mission of identifying effective treatment for prostate cancer that affects a large veteran population.