Targeting of the Hepatocyte Growth Factor Pathway for the Treatment for Breast Cancer

摘要

Hepatocyte growth factor (HCF), also known as Scatter Factor, induces cell growth and cell movement, and is known to promote invasiveness of malignant cells. It also promotes angiogenesis. HGF is known to be produced by fibroblasts within breast tumors, while its receptor, the c-Met protein, is expressed on the breast tumor cells themselves. HGF thus appears to act predominantly as a paracrine factor in breast cancer. High levels of HGF expression within breast tumors correlates with an aggressive tumor phenotype, and HGF has been found to be a powerful negative prognostic indicator for breast cancer. Expression of the c-Met protein by breast tumors in culture also correlates with an estrogen receptor negative phenotype and with loss of estrogen-dependent cell growth. Thus the HGF-c-Met ligand-receptor system may be important in controlling cell growth in breast tumors that have escaped estrogen regulation, a common occurrence in breast cancer patients who have lost responsiveness to anti- estrogen therapy. The hypothesis to be tested in this Idea Grant is that interruption of the HGF-c-Met signaling pathway will inhibit the growth of estrogen-independent human breast cancer cells and could be a useful therapeutic strategy for breast cancer patients who have failed endocrine therapy. We will use two approaches for these studies: (1) an anti-sense strategy that uses vectors constructed in the U6 RNA expression plasmid and delivered by cationic liposomes and (2) a recombinant HGF antagonist molecule (truncated HGF/tHGF) produced in baculovirus and delivered through injection to the peritumoral area.