Posted September 17, 2013
Alessandro Fatatis, M.D., Ph.D., Drexel University College of Medicine
PCRP Idea Development Award
Despite doctors' best efforts to diagnose, treat, and cure prostate cancer at an early stage, some patients eventually develop metastatic disease, which is responsible for more than 90% of prostate cancer deaths. In an effort to develop an effective and curative treatment of metastatic disease, the members of the team headed by Dr. Alessandro Fatatis at Drexel University are working to develop and use clinically relevant animal models with the goal of ensuring that research results from these models can be proficiently and rapidly translated into patient care. They are also working to identify and functionally validate molecular targets that could be used to develop new therapies for metastatic prostate cancer.
The team's previous work investigating the metastatic behavior of human cancer cells found that highly aggressive and metastatic cells express the highest levels of a protein called PDGFR-alpha (alpha-receptor for Platelet-derived Growth Factor). With support from a PCRP FY08 Idea Development Award, Dr. Fatatis and his team have been investigating the role of PDGFR-alpha in promoting metastatic behavior in prostate cancer cells, and testing potential PDGFR-alpha targeted therapies. The team has identified three genes that are directly regulated by PDGFR-alpha in prostate cancer cells, and further study of these genes indicated that the proteins encoded by these PDGFR-alpha-regulated genes are produced and secreted by cancer cells in order to recruit normal cells of the surrounding bone marrow. Once the bone marrow cells are recruited, they appear to aid the cancer cells by converting the tissue environment into an ideal niche for encouraging further growth and development of cancer cells, making PDGFR-alpha a good candidate for potential therapeutic targeting. Dr. Fatatis has also initiated pre-clinical studies to evaluate the potential of using PDGFR-alpha antibodies to target this pathway for treatment of metastatic disease, and their exciting, now published results show that blocking PDGFR-alpha dramatically impairs the bone-metastatic progression of prostate cancer cells as predicted, making this a promising option for further clinical testing. To help advance these findings further, Dr. Fatatis' group also plans to focus on the identification of the molecules implicated in this "cross-talk" between the cancer cells and normal cells, which could provide even more targets for future therapies to treat metastatic prostate cancer.
Studying experimental metastatic lesions that closely reproduce those observed in patients is paramount for our research. Human prostate cancer cells tagged with Green Fluorescent Protein are detected as single Disseminated Tumor Cells immediately after their arrival and homing to the skeleton of mice inoculated via the left cardiac ventricle (Top). These cells can be successively monitored during their progression into larger lesions, which can be identified in long bones and vertebrae (Bottom) and display dimensions comparable to metastases observed in humans.
Publications:
Russell MR, Qingxin L, Fatatis, A. Targeting the ∝ receptor for platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis. Clin Cancer Res. 2010;16:5002-10.
Liu Q, Russell MR, Shahriari K, Jernigan DL, Lioni MI, Garcia FU, Fatatis A. Interleukin-1β promotes skeletal colonization and progression of metastatic prostate cancer cells with neuroendocrine features. Cancer Res. 2013;73:3297-305