The aim of the research proposed in this application is to develop a new class of breast cancer therapeutics that neutralizes growth signals/growth factors rather than the cellular receptors that respond to these growth factors.

Many breast cancer cases result from cells being instructed to grow when they should not. This leads to uncontrolled cell proliferation and thus cancer. The incorrect growth instructions in a significant subset of breast cancers emanate from the HER2/ErbB2 protein, a well-known member of the family of "ErbB" receptors. When gene amplification causes an excessive number of HER2/ErbB2 molecules in the cell, its normally well-controlled growth signaling becomes aberrantly activated, leading to uncontrolled cell growth and cancer. The Herceptin antibody, used in the breast cancer treatment since 1998, targets HER2/ErbB2 and helps both to reverse this inappropriate growth signaling and to clear cells with this problem from tumors.

There are three other members of the same receptor family, which have different properties. One is the epidermal growth factor (or EGF) receptor, and increased levels of this receptor also have been reported in breast cancers and in other cancers. Agents that function like Herceptin or that inhibit EGF receptor in different ways have been generated and appeared very promising in preclinical studies. Unfortunately, these agents (e.g., Iressa, Tarceva, and cetuximab/Erbitux) have not had good responses in clinical trials in breast and other cancers, suggesting that the strategy that was successful for HER2/ErbB2 (with Herceptin) may not translate simply to the EGF receptor.

There are several reasons why this is not altogether unexpected. HER2/ErbB2 is always "primed" to be activated, and simply making too much of it in the cell causes it to activate cell growth. We and others have shown that the EGF receptor has its own internal "off-switch," which is absent from HER2/ErbB2 and stops EGF receptor from activating cell growth significantly unless its external stimuli (growth factors) are present. Thus, while directly targeting HER2/ErbB2 works well in the clinic, the situation is more complicated for EGF receptor, and only the activated form is worth targeting.

We seek to develop a new approach that targets the activating growth factors (Avastin, a new angiogenesis inhibitor does a similar thing for the vascular endothelial growth factor receptor) rather than targets the receptor. We recently showed that the fruit fly Drosophila melanogaster uses a mechanism in several stages of its development where it "neutralizes" the growth factors that activate its version of the EGF receptor. The fly does this by making a protein called Argos. Argos seeks out epidermal growth factor molecules and inactivates them. Our proposal involves adapting this molecule for use in treating human breast cancer cases. We have identified some human proteins that are related, and we will test their functions. We also have devised a strategy for converting the fruit fly Argos protein to one that will attack human growth factors and that therefore could be developed into a therapeutic molecule.

Thus, the ultimate applicability of our research would be manifest in a novel class of therapeutic molecules for treating breast cancer, specifically in cases where the EGF receptor or other members of this family are known to be present (and signaling) at high levels. It is difficult to judge what the time course of development might be. However, if our approach is successful, it should be possible to start preclinical animal studies with candidate molecules shortly after the 3-year grant period.