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The Transmembrane Protein Trop-2: An Attractive Target For Breast Cancer Therapy
Investigator Initiated Research
RATIONALE: Targeting oncogenes with antibodies has shown to reduce cancer recurrence and prolong survival. Despite the success of targeted therapeutics, the need to identify and develop novel therapeutic targets persists. We have recently shown that Trop-2 is an oncogene, and that it is required by breast cancer cells for tumorigenesis. Furthermore, as a transmembrane protein, it is accessible to antibodies.
HYPOTHESIS: We therefore hypothesize that Trop-2 plays a key role in breast tumorigenesis and that it is an attractive target for breast cancer therapy. We will test these hypotheses using several unique reagents and scientific approaches. These include a newly described monoclonal antibody to Trop-2 with anti-tumor properties, a recently created Trop-2 knockout mouse strain generated in our laboratory, and extensive tissue resources with which to study Trop-2 epidemiology. We expect that both antibody targeting and genetic deletion of Trop-2 will prove to have an anti-tumor effect, and our studies of Trop-2 expression in breast tumors will provide essential epidemiologic information required for further clinical development of anti-Trop-2 therapeutics.
SPECIFIC AIMS: (1) To examine the role of Trop-2 in breast cancer initiation and progression in mice. We will cross Trop-2 knockout mice with MMTV-Polyoma middle T (PyMT) and MMTV-Wnt-1 transgenic mice and evaluate the effects of Trop-2 deletion on the incidence, kinetics, and histology of breast tumorigenesis and metastasis. (2) We will test the efficacy of an inhibitory monoclonal antibody against Trop-2 in pre-clinical models of breast cancer. (3) We will characterize the epidemiology of Trop-2 expression in breast cancer. We will measure levels of Trop-2 RNA (by quantitative RT-PCR) and protein (by immunohistochemistry) in 300 annotated breast cancers and determine how these levels relate to clinicopathologic characteristics and breast cancer subtype.
HEALTH SIGNIFICANCE: This pre-clinical research will lay the foundation for the clinical development of anti-Trop-2 therapeutics. The Trop-2 monoclonal antibody to be tested is currently being humanized for clinical development (Arius Research Inc., Toronto, Canada) and should be available within the next 2 years. Given the ability of other targeted therapies to reduce cancer recurrence and prolong survival, we predict that a Trop-2 monoclonal antibody could have a similar effect in breast cancer.
Antibodies against cell surface proteins have proven to be highly efficacious in reducing breast cancer recurrence and can prolong survival in the case of metastatic breast cancer. We have identified a cell surface protein, Trop-2, that is required by some breast cancer cells in order to grow as tumors and have found that antibodies against this protein could block the invasive ability of tumor cells. These observations led us to hypothesize that Trop-2 is functionally important for breast cancer. We also hypothesize that Trop-2 is a treatment target for breast cancer, similar to proteins such as Her2Neu, against which the antibody Herceptin is highly effective. In fact, a biopharmaceutical company, Arius Research Inc., (Toronto, Canada) has developed a monoclonal antibody against Trop-2 that shows anti-tumor activity in prostate and ovarian cancer.
To test our hypothesis that Trop-2 is functionally important in breast cancer we will examine the effects of Trop-2 inactivation in breast cancer prone mice. To test the potential efficacy of a Trop-2 therapy in breast cancer, we have an agreement with Arius Research to perform the pre-clinical evaluation of their antibody against human breast cancers in mice. Finally, to identify the subset of patients who would benefit from anti-Trop-2 therapeutics, we will study the expression patterns of Trop-2 in breast cancer patients. Understanding both the percentage of breast cancer patients whose tumors exhibit high levels of Trop-2 and the relationship between Trop-2 expression and outcome will guide future clinical trials of a Trop-2 monoclonal antibody.
Importance to Breast Cancer Patients: Trop-2 is a protein that we have recently implicated in breast cancer and for which a potentially therapeutic antibody is available.
We have unique tools to study the role of this protein in breast cancer and more importantly, have the unique opportunity to be among the first groups to study the therapeutic effects of an antibody that targets Trop-2, a cancer causing protein. This work will pave the road for using antibodies against Trop-2 in breast cancer patients. Such antibodies should be ready for clinical testing within 2 years and may eventually prove to reduce breast cancer recurrence and prolong survival.