Project 172270

Much progress has been made over the last decade in our understanding of the cellular mechanisms leading to cancer. In spite of this, cancer still remains a major cause of human death. A novel anticancer therapy, based on the destruction of blood vessels within tumors, however offers new hope for the successful treatment of cancer. It is derived from the principle that tumor cells, like healthy cells, require oxygen and nutrients to survive. Thus, tumor cells release factors to act on nearby blood vessels to stimulate their growth into the developing tumor. This formation of new blood vessels, a process called angiogenesis, is essential for the aggressive growth of tumor cells, and allows their dispersal in the organism and the formation of metastases. To develop effective means of blocking the growth of tumor-associated blood vessels, we need to understand the molecular events that underlie their formation. In this context, we are proposing to deepen our understanding of the molecular mechanisms regulating angiogenesis with special emphasis on proteins called Gab1 and Gab2, which represent important signal amplifiers in cells. We have shown over the last funding period that these proteins play essential roles in the formation of blood vessels in vitro. Therefore, our goal for the next five years is to investigate their in vivo role during angiogenesis and tumor progression, and determine their potential as new therapeutic targets. To do this, we will generate mice in which the Gab1 and Gab2 genes are deleted from blood vessel cells, and we will investigate the consequences on angiogenesis, tumor-associated angiogenesis, and the ability of tumor cells to grow and metastasize. In a complementary fashion, we will also develop and test small peptide inhibitors that neutralize Gab1 and Gab2. The potential impact of these studies on the burden of cancer is that the knowledge generated may lead to the development of novel strategies to block angiogenesis and tumor growth.