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    Awarded Grants
    Targeting Indoleamine 2,3-Dioxygenase to Block Breast Cancer Metastasis

    Scientific Abstract:
    Title: Targeting indoleamine 2,3-dioxygenase to block breast cancer metastasis. Indoleamine 2,3-dioxygenase (IDO) is expressed by multiple cell types to suppress T-cell activity. We now have evidence that multiple breast cancer cell lines express IDO activity and that IDO protein is present in the lymph nodes containing metastatic breast tumors. The central hypothesis of the proposed research is that breast tumors induce IDO expression at the sites of metastasis, which induce T-cell tolerance and allow the establishment of metastatic cancer. Our long-range goal is to improve the therapy of breast cancer by targeting the tumor-induced immunosuppression. AIM 1. Evaluate the effect of inhibiting indoleamine 2,3-dioxygenase (IDO) activity on the metastasis of murine 4T1 mammary cancer cells. The working hypothesis for this aim is that blocking IDO activity will prevent breast cancer metastasis. We will inject 4T1 metastatic mouse mammary tumor cells into syngeneic Balb/c mice treated with slow release pellets containing 1-methyl-tryptophan (IDO inhibitor) or vehicle and determine its effect on metastasis. AIM 2. Identify the specific cell types that express indoleamine 2,3-dioxygenase in lymph nodes of breast cancer patients and correlate its expression with clinical parameters. The working hypothesis for this aim is that metastatic breast tumors communicate with the sentinel lymph nodes through the lymphatic fluid to recruit IDO expressing cells to the lymph nodes, which in turn induce T-cell tolerance and allow for the eventual establishment of metastatic colonies. It follows that IDO expression in lymph node tissue would be an important indicator of metastatic potential and would be useful to identify patients that would benefit from systemic therapy. We will conduct a retrospective study using immunohistochemistry to determine the IDO expression in lymph nodes of breast cancer patients. The proposed research is innovative because we are studying an immunosuppressive enzyme that is a novel target for breast cancer therapy and we are focusing on identifying high-risk patients based on tumor-immune system interactions. The potential benefits of the proposed research are 1) we are evaluating the effect of a drug that may inhibit breast cancer metastasis and 2) we are conducting the initial experiments in determining if lymph node IDO expression predicts the metastatic potential of breast tumors, even before there are detectable metastases. This would be particularly valuable in identifying node negative patients that would benefit from aggressive therapy.

    Lay Abstract:
    Title: Targeting indoleamine 2,3-dioxygenase to block breast cancer metastasis. One of the critical steps in the development of cancer is the suppression of the anticancer immune system. Likewise, one of the major limitations to the effectiveness of many types of therapies appears to be the tumor-induced immunosuppression. Our long-range goal is to improve the therapy of breast cancer by targeting the tumor-induced immunosuppression. Indoleamine 2,3-dioxygenase (IDO) is an important in regulator of the immune system. We now have evidence that breast cancer cells have IDO activity and that it is present in lymph nodes of patients with metastatic breast cancer. The central hypothesis of the proposed research is that breast tumors induce IDO expression at the sites of metastasis, which suppresses the immune system and allows the establishment of metastatic breast cancer. It follows that blocking the IDO activity would be an effective therapy for metastatic breast cancer. AIM 1. Evaluate the effect of inhibiting indoleamine 2,3-dioxygenase (IDO) activity on the metastasis of murine 4T1 mammary cancer cells. The working hypothesis for this aim is that blocking IDO activity will prevent breast cancer metastasis. To test this, we will use a mouse model that develops metastatic breast cancer. We will treat the mice with a drug,1-methyl-tryptophan to inhibit the IDO enzyme activity and determine if it will block the metastasis and cure the mice of their metastatic disease. AIM 2. Identify the specific cell types that express indoleamine 2,3-dioxygenase in lymph nodes of breast cancer patients and correlate its expression with clinical parameters. The working hypothesis for this aim is that metastatic breast tumors communicate with the lymph nodes through the lymphatic fluid to create a fertile and protected site for metastases before they actually establish metastases there. We will conduct a retrospective study to determine the IDO expression in lymph nodes of breast cancer patients and correlate it with important clinical parameters. The proposed research is innovative because we are studying the interaction of the tumor with the immune system and manipulating it in a way that represents a novel therapeutic strategy for breast cancer. The potential benefits of the proposed research are 1) we are evaluating the effect of a drug that may inhibit breast cancer metastasis and could eventually be translated into a breast cancer therapy, and 2) we are conducting an initial experiment to determine if we can identify patients that would benefit from aggressive therapy.