A peptide antagonist of chemokine receptor CXCR4 reduces tumor metastasis in a murine orthotopic model of human prostate cancer

Proc Amer Assoc Cancer Res, Volume 47, 2006 2162 Prostate cancer is the second most common form of cancer in America and a leading cause of cancer-related deaths in men. The cure rate declines dramatically once the cancer metastasizes from the prostate glands to distant sites in the body. The main target for prostate cancer metastasis is bone. Prostate cancer cells are also commonly found in other organs surrounding the prostate area including the seminal vesicle, lymph nodes in the groin area and the rectum. Reports in the literature indicate that the expression of the chemokine receptor CXCR4 by prostate cancer correlates to their metastatic potential. CXCR4 is the receptor for the chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1). The expression of SDF-1 is especially high in the bone marrow and is related to hematopoiesis. Cancer cells expressing CXCR4 home in to SDF-1 in the bone marrow and other specific organs. We have synthesized a number of analogs of SDF-1 using rational based drug design and some of these analogs have been shown to be antagonists of CXCR4. The lead compound of these synthetic antagonists, known as CTCE-9908, was tested in a murine orthotopic model of human prostate cancer (PC-3) for its ability to reduce metastases. Before initiation of in vivo studies, PC-3-GFP cells were mounted on poly-L-lysine-coated slides and stained with an anti-CXCR4 antibody. Varying degrees of CXCR4 expression was observed in all PC-3-GFP cells. For in vivo studies, two 1mm3 fragments of viable PC-3-GFP tumors harvested from the subcutaneous maintenance site of nude mice were sutured between two ventral lobes of the prostate in nude mice. Three days after tumor implantation, daily CTCE-9908 injections at a dose of 25 mg/kg/day IP or SC was initiated. Control mice received injections of vehicle. Mice were sacrificed after 4 weeks of treatment or when moribund. The fluorescent tumor pattern was then imaged. Analyses showed that the total area of metastasis was reduced from 370mm2 to 160mm2 for IP, and 130mm2 for SC. Reductions of 58% and 64%, respectively. This is consistent with findings of metastasis inhibition in other models including osteosarcoma, melanoma, and lung carcinoma. Further studies are in progress to determine optimal dose, scheduling, and combination with current therapies in this model. A phase I study has shown safety in healthy adults. A phase Ib/II study is expected to be initiated this year. The results to date suggest that the continued study of CTCE-9908 against a variety of metastatic tumor types is warranted.