Neo-vascularization (angiogenesis) and inflammation in the tumor microenvironment have been described as favorable for tumor cell growth and survival. As a direct result, tumor cells are able to travel through the circulation to colonize distant organs and sites (metastases). A natural protein known as Pigment Epithelium-Derived Factor (PEDF) is expressed in normal tissues and decreased in prostate tumors. We have shown that PEDF is a potent angio- inhibitory factor. Other studies suggest a role for PEDF in inflammation;however its precise mode of action is still unclear and need further investigation. In a previous work, we demonstrated that engineering prostate cancer cells to increase PEDF blocks tumor growth and prolong survival in vivo. We also have shown that PEDF stimulates the recruitment of monocytes and macrophages inflammatory cells in vitro. Thus PEDF expression, prostate cancer progression and tumor inflammation seem interrelated. However, their precise relationship during prostate cancer growth and metastasis formation is still unclear. In the proposed study, we will first evaluate in mouse prostate cancer models, the capacity of PEDF to block the formation of bone metastases, a common and therapeutically challenging site of disease in patients with advanced prostate cancer. We will also identify the mechanisms by which PEDF expression affects the anti-tumor immunity activity in human prostate cancer. We will evaluate the in vitro and in vivo anti-tumor activities of PEDF in combination with low dose taxane drugs. The taxane drugs are currently used as standard chemotherapies for patients with metastatic prostate cancer. These studies which combine both in vitro, in vivo and mouse preclinical models, should allow us to provide data in support of PEDF as novel target for prostate cancer treatment. We also anticipate that this project will lead to the development of improved therapeutic approaches for prostate cancer.
The major goals of this project are to validate PEDF as a novel therapeutic target for prostate cancer and to investigate PEDF anti-cancer efficacy in combination with low dose chemotherapeutic taxane drugs in preclinical models of prostate cancer. We will also identify the mechanisms by which PEDF affects the anti-tumor immunity activity in human prostate cancer.
|Nelius, T; Martinez-Marin, D; Hirsch, J et al. (2014) Pigment epithelium-derived factor expression prolongs survival and enhances the cytotoxicity of low-dose chemotherapy in castration-refractory prostate cancer. Cell Death Dis 5:e1210|
|Nelius, Thomas; Samathanam, Christina; Martinez-Marin, Dalia et al. (2013) Positive correlation between PEDF expression levels and macrophage density in the human prostate. Prostate 73:549-61|