Invasiveness and metastasis are the most insidious and life-threatening aspects of breast cancer. Although less than 10% of women with primary breast cancer have clinical symptoms of obvious metastasis, metastatic relapse occurs in about half the cases within five years of surgery, and in 23% of the patients, bone marrow metastases are detectable at first relapse. Why does treatment fail? One reason for treatment failure could be that we are tailoring treatment against the primary tumor while metastases may be quite different in their behavior and genetic makeup. Also, most current therapies are designed to kill the carcinoma cells, while we now recognize that tumor cell response to treatment is also determined by the stromal cells (endothelial cells lining the blood vessels, fibroblasts and lymphocytes) supporting its growth. This proposal aims to bring together experts in the area of vaccine and drug therapy to develop targeted (gene-based) combination therapies for metastatic breast cancer. (1) The vaccine-based approach is to use a combination of tumor cell vaccines, antibodies and drugs aimed at epithelial and endothelial cells in the tumor. (2) Drug combinations of aromatase and COX-2 inhibitors along with new targets will be tested against local and metastatic breast cancer. (3) New target information will come from gene searches by a method called SAGE performed on purified cell populations (epithelial, endothelial and stromal fibroblasts) from bone and lung metastasis that will identify genes that are over- or underexpressed in bone and lung metastasis. These genes/gene products could be developed as early detection markers for hidden metastasis and as targets for vaccine and drug development. (4) A protein search effort (by Phage Display) will identify peptides that can be used for targeting noxious drugs solely to the cancer, for targeting radiologic agents for detection and treatment of hidden metastasis, and for identifying tumor-specific antigens against which vaccines and antibodies could be developed. (5) Finally, to gauge tumor response, particularly to anti-angiogenic therapies, non-invasive imaging is required technology, since there is no change in tumor size in the early stages of therapy. The last project will study tumor responses to anti-angiogenic agents, with potential clinical value, by magnetic resonance imaging (MRI). It will also determine if cross talk between endothelial and cancer cells (and the abnormally expressed genes in them from Projects 1 and 2) impacts on invasion and metastasis caused by physiological stress, such as low oxygen. Thus, each of these projects complements the effort of the others by providing expertise and reagents for testing of the concepts presented. Integral to this effort is the active participation of four survivor advocates and three resources (core facilities) providing administration, communication, biostatistics and bioinformatics support. In addition, a new program will be launched for the first time, with education, outreach and recruiting help from our survivor volunteers, called the rapid autopsy program (RAP) for collecting metastatic tissues soon after death with the consent of the patient and their relatives. This endeavor will enable studies on metastasis which have been stalled for years due to the meager availability of tissue for the COE and for future generations of researchers.

The ultimate applicability of this research will be in treatment of metastatic breast cancer. If breast cancer patients could receive treatment that erodes the cancer cells' ability to settle elsewhere, and destroys hidden deposits of cancer in the rest of the body, the chance of recurrence would be very low. The treatments are likely to help patients who have not responded to current therapies. The potential clinical applications of the technologies are clear in the development of imaging agents and knowing which genes are unique to metastasis and are vulnerable to specific vaccines and drugs; and devising early detection strategies (not pursued in this grant). The benefits of this work are clear, while the risks will become clear as the preclinical studies progress. It is projected that Phase 1 trials for both the vaccine cocktail and combinations of COX-2 and aromatase inhibitors will be initiated by year 5.

Thus, we believe that we have brought together a dedicated group of experts in different areas of breast cancer research from Johns Hopkins and the University of MD School of Medicine, recruited new talent who has made a huge impact in other cancer types (Dr. Pasqualini, UT MD Anderson Cancer Center), and provided an umbrella of essential core resources to serve as a conduit of rapid communication and exchange of reagents. Very importantly, we work intimately with consumer advocates who have their thumb on the pulse of what is urgently needed in the community, and who will serve actively in our COE. Thus, we feel, we will provide the platform for groundbreaking research in the understanding of, and treatment of metastatic breast cancer.