Project 2:
Molecular Determinants of Response to RTK Pathway Inhibitors

Co-Principal Investigators - Joe W. Gray, PhD | Frank McCormick, PhD, FRS
Clinical Co-Principal Investigator - Hope Rugo, MD

Deregulation of receptor tyrosine kinase (RTK) signaling is now recognized as important in the genesis and progression of human epithelial cancers, including breast cancer. This knowledge has stimulated the development of a broad range of RTK pathway inhibitors as anticancer agents. Iressa (ZD-1839) and Herceptin are two examples that are now in clinical use. Unfortunately, responses to these and other RTK inhibitors vary dramatically, even between patients that over express the target receptor. We postulate that this is due, in part, to the considerable variation in RTK pathway function that occurs downstream of the receptor. We believe that aberrations that will interfere with response to upstream RTK inhibitors and/or that predict unexpected response can be detected by analysis of a collection of 60 breast cancer cell lines that carry the same spectrum of RTK pathway aberrations as found in primary breast tumors. Use of cell lines to predict inhibitor response failure is attractive because of the savings in cost and time and because the information can be obtained before early phase clinical trials begin so that it can be used to guide trial design. Thus, the central goal of this project is to test this hypothesis. Should this approach prove out, it would have broad utility for development of predictive strategies for the wealth of RTK inhibitors and other targeted therapeutics that are now under development and would substantially increase the speed and decrease the cost of agent trials. This will be accomplished in three aims.

1. Biological responses and molecular profiles will be measured before and during treatment with Iressa and Herceptin for 60 breast cancer cell lines and analyzed to identify aberrations that interfere with Herceptin- or Iressa-induced changes in mitotic index, motility, growth rate, and/or apoptotic rate.

    

2. Molecular predictors of response developed in Aim 1 will be tested in vitro by modulating the expression of RTK pathway genes predicted to influence response to Herceptin and/or Iressa and in vivo by examining biological and clinical responses of human breast cancer xenografts.

    

3. Predictors of response will be tested in 200 patients treated with Herceptin as a single agent and, if successful, in ~1400 samples from patients enrolled in the NSABP B-31 trial in which samples are being collected from 2700 patients treated with chemotherapy +/-Herceptin. Predictors of response to Iressa will be tested in 40 patients treated with Iressa as a single agent.