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Breast Preclinical Research Program
The Breast Preclinical Research Program focuses on basic science research of breast cancer. The program includes several research teams that are exploring novel breast cancer medications, therapeutic targets, diagnostic biomarkers and sophisticated investigations of the molecular basis for rational and targeted therapies.
In collaboration with Lucio Miele, MD, PhD, Director of the University of Mississippi Medical Center Cancer Institute, researchers at the Cardinal Bernardin Cancer Center (CBCC) have pioneered novel research in "Notch” genes in breast cancer. This research guides the development of novel medications that already are in clinical trials. The research also aids the discovery of additional ways to target these genes to prevent or treat resistance to antiestrogens and to the drug trastuzumab. It appears that these Notch genes represent an emergency escape mechanism that is triggered by treatment with diverse breast cancer drugs and then helps cancer cells survive.
Promising therapeutic combinations developed at the CBCC eventually will be offered to patients in the clinical research setting by the Breast Clinical Research Program team. Kathy Albain, MD, Constantine Godellas, MD, Prabha Rajan, MD, and other members of the program are developing novel genetic tests that can better define the potential for recovery of breast cancer patients. The preclinical research group also participates in clinical trials initiated by clinical research program physicians by evaluating novel molecular markers in patient biopsies or surgical specimens.
Notch and breast cancer cells
Approximately 80 percent of breast cancers are defined as "estrogen receptor positive" or estrogen-positive tumors. Patients with estrogen-positive tumors are treated with drugs that block the estrogen receptor or block the body's production of estrogen. However, some cancers do not respond well to this treatment, and some become resistant and the cancer recurs after initially responding. This is a major clinical problem.
Research by Paola Rizzo, PhD, assistant professor, Stritch, Department of Pathology, has determined that estrogens block the activity of "Notch receptors" in breast cancer cells. Conversely, when breast cancer cells are treated with drugs such as tamoxifen that block estrogen inhibitors, the cancer cells respond by reactivating the Notch receptor. These help breast cancer cells survive and could make the cells more resistant to further treatment.
Based on these studies, it has been determined that a combination of anti-estrogen medication plus a new drug that blocks Notch receptors can make estrogen receptor positive tumors shrink and disappear (in studies in mice). A clinical trial of a similar combination is planned at Loyola in the near future and may open the way to the development of new treatment regimens.
Her2/Neu oncogene and Notch
Approximately 30 percent of breast cancers are very abundant with the Her2/Neu (or ErbB2) cancer receptor. These cancers tend to be clinically aggressive and are often not responsive to drugs that block estrogen receptors. Currently, treatments for these cancers include trastuzumab and lapatinib, a newer drug that blocks the enzymatic activity of the Her2/Neu protein and other related receptors.
Research by Clodia Osipo, PhD, assistant professor, Stritch, Department of Pathology, has determined that treating the Her2/Neu positive breast cancer cells with trastuzumab or with a class of drugs similar to lapatinib leads these cancer sites to respond by re-activating these Notch receptors, just as observed for estrogen-blocking drugs. The Notch receptors help breast cancers survive and possibly become resistant to trastuzumab or lapatinib.
Studies conducted in cells grown in the laboratory have shown that when a new drug that blocks Notch receptors is given along with the drugs trastuzumab or lapatinib, their effectiveness is greatly increased. If preclinical research proves effective, planning for clinical trials will begin.
Breast cancer stem cells
The preclinical research group that Kimberly Foreman, PhD, associate professor, Stritch, Department of Pathology, directs is studying the newly discovered “breast cancer stem cells,” rare cells that give rise to breast cancer recurrences and metastasis (the spread of cancer) and studying novel ways to eradicate these cells. Stem cells have the remarkable potential to develop into many different cell types in the body. Additionally, Dr. Foreman is investigating normal human adult stem cells not derived from human embryos, and the "communication" between breast cancer cells and blood vessels.
Psychological stress reduction techniques
Herbert Mathews, PhD, professor, Stritch, Department of Microbiology & Immunology, directs a group that is conducting cutting-edge research on the effects of psychological stress reduction techniques, such as the mindfulness awareness program, on breast cancer patients’ immune systems. Understanding this aspect of the mind-body connection will improve our ability to increase patient well-being and the effects of treatment.
Adriano Marchese, PhD, assistant professor, Stritch, Department of Pharmacology & Experimental Therapeutics, leads a group in his department that is studying the function of CXCR4, a receptor that is crucial for metastatic spread of breast cancer cells through the body. His work may lead to the discovery of novel agents that prevent such metastasis, or the spread of cancer.
The preclinical research program also takes advantage of constant collaboration with Chindo Hicks, PhD, and Leo Wang-Kit Cheung, PhD, both assistant professors at Stritch, Department of Preventive Medicine & Epidemiology. The two are internationally renowned experts in bio-informatics, the discipline that uses highly powerful computer algorithms to study.