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    Awarded Grants
    Metabolic Imaging of Breast Cancer Glycosylation

    Scientific Abstract:
    Background: Aberrant glycosylation is a feature of tumor cell surfaces that could be exploited for targeted diagnostics. Numerous breast cancers express elevated levels of glycans bearing the monosaccharide sialic acid. Consequently, the upregulation of cell surface sialic acid is a feature shared by many breast cancers. The enzymes that biosynthesize sialic acid from its precursor ManNAc are toleratant of modifications to the N-acetyl group. Thus, an azido analog of ManNAc (ManNAz) is metabolized to the corresponding unnatural sialic acid (SiaNAz) in living animals. We developed a reaction termed the Staudinger ligation that can selectively target azides with phosphine probes in living animals, enabling the delivery of reagents to cell surfaces rich in sialic acid. Objective/Hypothesis: We propose to develop a novel breast cancer imaging method based on metabolism of of ManNAz to SiaNAz followed by selective targeting of richly sialylated tissues with phosphine-conjugated imaging reagents. Specific Aims: The objectives of the proposal are three-fold: 1. Evaluate the metabolism of ManNAz in murine breast cancer models. 2. Determine the efficiency of the Staudinger ligation on breast cancer tissue in vivo. 3. Develop phosphine probes for non-invasive imaging of breast cancer. Study Design: Tumor-bearing and healthy mice will be administered a prodrug form of ManNAz, and the resulting levels of SiaNAz on breast cancer and normal tissue will be quantified. The ability to target these azides with phosphine-conjugated radioligands and fluorescent probes will be investigated using non-invasive radionuclide and fluorescence imaging, respectively. Potential Outcomes and Benefits of the Research: The proposed work focuses on the development of a novel imaging strategy for the early diagnosis of breast cancer. Changes in glycosylation are thought to occur early in the progression of cells to a malignant state. Thus, imaging techniques that exploit cell surface glycosylation could have benefits over conventional imaging methods.

    Lay Abstract:
    Background: All cells are coated with complex sugar molecules, but the structures of those sugars vary as a function of cell type and state of health. The sugars found on cancer cells are known to be structurally distinct from those on normal, healthy tissue. For example, one component of complex sugars termed “sialic acid” is more abundant on breast cancer cells than on their normal healthy counterparts. We plan to exploit the abundance of sialic acid on breast cancers in order to visualize the cancer cells when the tumor is still in its earliest stages. Objective/Hypothesis: The goal of this project is to investigate how the differences in sugars on breast cancer cells might be exploited for early detection using non-surgical methods and, ultimately, for anti-cancer therapy. Specific Aims: Our approach exploits a recent discovery from our lab, that normal sialic acid on cells can be replaced with a modified form of that sugar by feeding cells a simple precursor sugar. The simple precursor is chemically modified so that, once converted to sialic acid and presented on cancer cells, it can serve as a “chemical handle” for targeting with diagnostic probes. A goal of this project is to develop methods for targeting breast cancers with the unnatural sugar followed by probes that can be detected by X-ray imaging or PET scanning. Study Design: We plan to investigate the viability of the proposed non-invasive diagnostic method in mouse tumor models. Mice will be treated with an unnatural sugar that we have shown in previous work to be non-toxic. The unnatural sugar will be metabolized to an unnatural form of sialic acid, and the abundance of that sialic acid on breast cancer and normal tissue will be determined. Next, we will target the unnatural sialic acid with probes that can be visualized inside the animal using non-invasive methods. Potential Outcomes and Benefits of the Research: The proposed project has several innovative elements and potential benefits. First, this would be the first method to exploit cancer-specific changes in cell surface sugars for non-invasive imaging of tumors. Second, the method involves innovative chemistry for targeting imaging probes to the cancer cell surfaces. The combination of chemistry designed to occur in the human body with an understanding of how sugars change on cancer cells is a unique feature of this project.