Annexin II expression is lost during progression of prostate cancer from the prostate intraepithelial neoplasia (PIN) stage to cancer. Annexin II functions both at the cell surface and in the nucleus: At the cell surface, Annexin II organizes a proteolytic center proposed to regulate angiogenesis, tumor invasion and metastasis. Annexin II in the cell nucleus regulates cell proliferation and DNA synthesis. The long-term goal of our research program is to identify the key molecular events that lead to development and progression of prostate cancer, in order that improved detection methods and therapies to treat this disease can be developed. The objective of studies outlined in this application is to determine if replacement of the Annexin II gene results in inhibition of prostate cancer growth and angiogenesis. Our central hypothesis is that the nanoparticle-mediated sustained expression of Annexin II gene would lead to prolonged accumulation of Annexin II in the nucleus resulting in inhibition of cell proliferation and sustained cell surface Annexin II expression resulting anti-angiogenesis, collectively inhibiting prostate cancer growth. We propose the following specific aims:
Aim 1 : To determine the in vitro effect of nanoparticle-mediated Annexin II delivery on phenotypes associated with prostate cancer growth. The working hypothesis for this aim, based upon preliminary data, is that sustained nanoparticle- mediated nuclear accumulation of Annexin II results in inhibition of prostate cancer cell proliferation.
Aim 2 : To determine the effect of nanoparticle-mediated Annexin II delivery on growth and angiogenesis of prostate tumors in a mouse model system. The working hypothesis for this aim is that sustained delivery of the anti-angiogenic Annexin II to prostate tumors in mice leads to reduction in tumor number and volume, and prolongs animal survival. These studies are innovative in that we are proposing a new approach of Annexin ll-based therapy for prostate cancer. At the completion of this project, it is our expectation that we will have determined that the nanoparticle-mediated sustained Annexin II gene delivery would result in retardation of prostate growth and reduced tumor burden.
