The main focus of my laboratory is to understand the role of angiogenesis in growth of tumors. It has been recognized for decades and now confirmed that growth and development of tumors is dependent on angiogenesis. In this context, Folkman’s laboratory identified angiostatin in 1994, one of the first and most potent inhibitor of angiogenesis known to date. Angiostatin treatment has resulted in the complete regression of human tumors implanted into nude mice. Angiostatin is currently being evaluated in clinical trials against the cancer. Currently the mechanism by which angiostatin inhibits angiogenesis and tumor growth is unknown. Unfortunately, we are unable to make bioactive angiostatin for therapeutic use. If target or receptor(s) were known, highly specific and potent smaller molecules can be developed. These molecules that could land on the receptor and do what the whole molecule does. This will open the door for biochemist/chemist to design the mimetic for angiostatin.

In an attempt to begin to understand angiostatin's mechanism of action our laboratory has made the striking discovery that a 35kDa protein/receptor expressed in endothelial cells which binds angiostatin is annexin II. Annexin II is one of the most abundant endothelial cell surface fibrinolytic receptor for plasminogen. Our laboratory discovered that anti-annexin II antibody mimics the angiostatin effect and inhibits endothelial cells (EC) proliferation and induces cell death in a dose dependent fashion. We have demonstrated that targeted disruption of annexin II by monoclonal (MAbs) inhibits angiogenesis in vitro and tumor growth in mice. This observation provides a great deal of hope that functional mimetics of angiostatin can be derived by developing MAbs. Our laboratory is developing these antibodies as a therapeutic molecule for war against cancer. Our laboratory is also engaged in identifying the expression of cell cycle regulatory proteins in endothelial cells, their regulation by growth factors and role in angiogenesis.

Publications:

1.George P. Tuszynski M.R Sharma, Vicki L. Rothman, and Mahesh C. Sharma, (2002). Angiostatin binds tyrosine kinase substrate annexin II through lysine binding domain in endothelial cells Microvascular Research (in press)

2.George P. Tuszynski, Meena R. Sharma, Vicki L. Rothman and Mahesh C. Sharma (2002). Over- expression of annexin II in invasive breast cancer cells in vitro and ductal carcinoma in vivo Proc. Am. Assoc. Cancer Research 43, A#129

3.M.C. Sharma, Meena R. Sharma, Vicki L. Rothman, George P. Tuszynski, (2002). Targeted disruption of annexin II inhibits angiogenesis in vitro and tumor growth in vivo Proc. Am. Assoc. Cancer Research 43, A# 894

4.George P. Tuszynski, Vicki L.Rothman, jing Zhou and M.C. Sharma (2001). Angiocidin, a new tumor inhibitor. Proc. Am. Assoc. Cancer Research 42, 568, A# 3048