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    Awarded Grants
    Control of Breast Cancer Metastases by Photodynamic Therapy

    Scientific Abstract:
    Breast cancer is the most common cancer diagnosis in American women. Over 200,000 women are diagnosed with invasive disease each year, and 20% of these women die from metastatic disease. Treatment of metastatic breast cancer is still problematic even after years of advancement in breast cancer research. There have been some successes in the use of oncogene-targeted immunotherapy for the treatment of metastatic breast cancer. For example, herceptin, an anti-HER2 monoclonal antibody, has shown some promise as a treatment for metastatic breast cancer. However this therapy is limited to breast cancers that overexpress the HER2 receptor, which only accounts for about 15 to 25 % of human breast cancers. Other therapies such as hormonal therapies are effective for cancers expressing the appropriate receptors. Patients whose cancers do not meet the criteria or whose cancers have lost receptor expression do not benefit from these therapies. Photodynamic therapy (PDT) is an established therapy for the treatment of various types of cancer. It uses a combination of light and photosensitizing drugs to induce damage to tumor tissue. The mechanism of PDT tumor destruction involves a complicated combination of direct cytotoxicity to the tumor cells and secondary-damaging events caused by vascular shut down, and inflammation. These effects of PDT culminate in the induction of a specific host anti-tumor immune response. The enhanced immune response appears to be tumor specific and T cell dependent. Pre-clinical and clinical studies have shown that tumor control by PDT correlates with induction of anti-tumor immunity. We have shown that the PDT induced anti-tumor immune response is able to control secondary disease. The mechanism by which PDT enhances anti-tumor immunity is unknown. However both direct and indirect effects of PDT on tumor cells are involved. Direct treatment of tumor cells in vitro by PDT enhances tumor cell immunogenicity and tumor cell lysates generated by PDT are effective vaccines. We have proposed to test the hypothesis that PDT treatment of primary mammary tumors enhances a specific anti-tumor immune response and results in control of secondary metastatic disease. To test this hypothesis we will use the 4T1 murine mammary carcinoma, which is a highly malignant tumor that spontaneously metastasizes to lymph nodes, lungs, brain, liver, and blood. The disease progression of 4T1 tumors parallels highly invasive metastatic human breast cancer very closely. It is therefore an excellent model for human breast cancer. The primary tumor will be treated with PDT, and the effects of local treatment on the metastatic disease will be assessed. We predict that PDT treatment of the primary tumor will result in an enhanced anti-tumor immune response that will cure the primary tumor and reduce metastatic tumor load. This study will further investigate the underlying mechanism through which PDT enhances an immune response against mammary tumors.

    Lay Abstract:
    Breast cancer is the most common cancer diagnosis in American women. Over 200,000 women are diagnosed with invasive disease each year, and 20% of these women die from metastatic disease. Treatment of metastatic breast cancer is still problematic even after years of advancement in breast cancer research. There have been some successes in the use of antibodies for the treatment of metastatic breast cancer. For example, herceptin, is an antibody that has shown some success in controlling metastatic breast cancer. However this therapy is only effective for breast cancers that overexpress the HER2 receptor, which only accounts for about 15 to 25 % of human breast cancers. Similarly, hormonal therapies are effective for cancers expressing the appropriate receptors. Therefore, patients whose cancers do not meet the criteria do not benefit from these therapies. Photodynamic therapy (PDT) is an established therapy for the treatment of various types of cancer. It uses a combination of light and photosensitizing drugs to induce damage to tumor tissue. The mechanism of PDT tumor destruction involves a complicated combination of direct tumor cell death and secondary events caused by damage to the tumor blood vessels and stimulation of inflammation. These effects of PDT culminate in the induction of a specific host anti-tumor immune response. Recent studies have shown that PDT enhances the immune response to mammary tumors. We have shown that this response is effective against secondary disease. In the proposed study, we will test the hypothesis that induction of an immune response against mammary tumors by PDT will control the growth of spontaneous lung metastases. To test this hypothesis, we will use a mouse mammary carcinoma model that is highly malignant and spontaneously metastasizes to lymph nodes, lungs, brain, liver, and blood. The disease progression of this tumor model parallels invasive metastatic human breast cancer very closely. It is therefore an excellent model for human breast cancer. The primary tumor will be treated with PDT, and the effects of local treatment on the metastatic disease will be assessed. We predict that PDT treatment of the primary tumor will result in an enhanced anti-tumor immune response that will cure the primary tumor and reduce metastatic tumor load. This study will further investigate the underlying mechanism through which PDT enhances an immune response against mammary tumors.