The ultimate goal of this study is to develop better screening, diagnostic, and treatment options for people suffering with breast cancer. Our strategy to accomplish this is to develop novel and pain-free methods that identify cancer-associated immune cells and/or substances they release ("proteases") in a patient's breast tissue. In doing so, we will be able to determine whether targeting these immune cells or inhibiting their proteases with drugs will benefit the patient by limiting cancer development and extending life span.
Background: Scientists have known for some time that when cancerous cells develop in a tissue, some characteristics of that cancer-containing tissue resemble a normal tissue undergoing wound healing. One of these characteristics has to do with the presence of noncancerous immune cells in that tissue. Under "normal" circumstances, immune cells are important because they help the body fight infections and aid tissues in healing after a wound. Immune cells help tissues heal by releasing substances (growth factors and proteases) that aid growth and repair of tissues. When cancers develop, they can, however, be perceived by that tissue as a wound. When this occurs, specific types of immune cells will move into the tissue as part of a natural wound response. But instead of promoting a "healing response," the growth factors and proteases released by these immune cells will instead help the cancerous cells grow. Our research indicates that cancer development can be slowed and sometimes halted by limiting immune cell activities, like growth factor and protease release, in tissues.
Objectives: The study objectives are to (1) determine which immune cells and proteases are most likely to be involved in human breast cancer development; (2) determine the best way to identify immune cells and proteases in human breast cancers; and (3) develop compounds that can be used to identify cancer-promoting immune cells or proteases in tissues by noninvasive (without surgery) imaging. This preclinical study will be performed in the laboratory using cells, mouse models, and human breast cancer biopsies in order to test these new strategies and imaging methods before trying them on people.
Implications for Breast Cancer Detection and Treatment: Breast cancer is the most frequent malignant tumor of women in North America. While standard treatments have improved life span and quality of life for women with breast cancer, the fact that 40% still succumb to disease highlights the need for new therapeutic approaches and identification of new therapeutic targets. Scientific studies indicate that some immune cells induce precancerous cells to develop into life-threatening cancers; thus, it is our belief that manipulating how immune cells respond and neutralizing their effect on cancerous cells, will provide a successful alternative approach to current disease management. The first step in assessing this belief is to develop novel and innovative technologies to image immune cells and their proteases in precancerous and cancerous tissues without having to do surgery (noninvasive). Developing this capability will allow physicians to identify precancerous growths in a woman's breast that are at the highest risk for developing into a malignant cancer. This ability will help the physician tailor a treatment plan with appropriate drugs and will allow monitoring how the patient's "tumor" responds to those drugs through noninvasive imaging.
We hypothesize that the profile of inflammatory cells and their proteolytic mediators constitutes an independent regulator of mammary epithelial cell behavior during breast carcinogenesis and that neutralizing the effects of innate immune cells during premalignancy will provide a therapeutic advantage and extend life span. Moreover, we predict that development of noninvasive imaging reagents that selectively image immune cell status and/or proteolytic activity in vivo will provide valuable diagnostic tools with which to predict clinical outcome and to evaluate efficacy of noncytotoxic host-targeted therapeutics.
The proposed Era of Hope Scholar Award will identify inflammatory leukocytes and proteases associated with breast cancer progression, identify those that play causal roles in disease initiation and progression, and develop approaches for noninvasive imaging of their functional status in vivo. Together, these will enhance identification of neoplastic breast lesions and ultimately result in optimized treatment protocols tailored to the leukocytic and/or proteolytic profile of an individual patient's breast cancer.
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