Despite recent additions in the clinical armamentarium of drugs for prostate cancer (PCa) therapy, hormone refractory metastatic disease accounts for an overwhelming majority (~90%) of PCa deaths with skeletal metastases, particularly in bones. Most currently-available chemotherapeutic regimens for PCa including docetaxel essentially target rapidly dividing cell populations non-selectively, thus presenting debilitating toxicities. Other major limitations are owing to the emergence of androgen-independence as well as lower proliferative capacity of the metastatic disease. Thus, identification of novel molecular targets that are selectively presented by the less-proliferative, androgen-independent metastatic prostate cancer cells might result in the near-complete elimination of this dreaded disease. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively over expressed in prostate cancers with negligible expression in normal prostate epithelia. Our recently published and preliminary data demonstrate that 1) CCR9 is highly expressed by PCa cells and mediates PCa cell migration, invasion and survival in vitro, 2) CCR9 is also highly expressed in clinical prostate cancer tissue samples, 3) CCL25, a natural ligand of CCR9, is expressed in a paracrine manner by PCa clinical sample and also elevated in PCa patient serum, 4) bone marrow stromal cells of tumor-bearing mice significantly produce CCL25, compared to non-tumor bearing ones, 5) inhibition of CCR9-CCL25 axis sensitizes cellular responses to chemotherapy in PCa cells. Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis plays a crucial role in prostate cancer metastasis and is a cancer-selective therapeutic target. Targeting this axis will enable development of new chemotherapeutic strategies as well as improving existing ones by sensitizing prostate cancer cells to currently available regimens. To validate our hypothesis, we propose to determine the role of CCR9-CCL25 axis in (i) inducing prostate cancer cell migration and invasion, (ii) prostate cancer cell survival and apoptosis, (iii) triggering prostate cancer growth and metastases iv) enhancing chemotherapeutic efficacy of clinical regimens. To accomplish our aims, we have generated CCR9 conditional knockout cells that will be used for in vitro assays to determine its role in PCa cell migration, invasion and survival, and determining its potential role in tumor growth, metastasis and therapeutic efficacy of docetaxel. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to evaluate the role of CCR9-CCL25 axis in promotion of metastases. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa and will go a long way to enhance our understanding of chemokines in mediating disease aggressiveness. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 axis for PCa.

SC1CA180212

2013-04-01

2021-03-31