NOVEL SMALL MOLECULE INHIBITION OF DDR2 TO PREVENT BREAST CANCER METASTASIS

新型小分子抑制 DDR2 预防乳腺癌转移

• 批准号: 9026185
• 负责人: Gregory D. Longmore
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026185
• 关键词: Architecture; Basic Science; Binding; Binding Sites; Biology; Blood Vessels; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer cell line; Breast cancer metastasis; Cell Proliferation; Cell Surface Receptors; Cell physiology; Cells; Cessation of life; Clinical; Clinical Data; Collagen; Collagen Receptors; Complex; DDR1 gene; Data; Development; Dimerization; Disease; Drug Targeting; Ductal; Environment; Epithelial; Epithelium; Extracellular Domain; Fibrillar Collagen; Fibroblasts; Genetic; Growth Factor; Human; In Vitro; Integrins; Investigation; Kinetics; Ligand Binding; Ligands; Lymphatic; Malignant Neoplasms; Mammary Neoplasms; Mediating; Molecular; Molecular Target; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Prevention; Prevention therapy; Primary Neoplasm; Process; Protein Tyrosine Kinase; Proteins; Reagent; Receptor Protein-Tyrosine Kinases; Regulation; Safety; Signal Transduction; Site; Stromal Cells; Stromal Neoplasm; Structural Protein; Structure; Testing; Therapeutic; Toxic effect; Tumor Cell Invasion; Tumor Subtype; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; Woman; Work; base; cytokine; discoidin domain receptor 2; effective therapy; extracellular; humanized antibody; in vivo; inhibitor/antagonist; interstitial; malignant breast neoplasm; migration; neoplastic cell; novel; organ growth; prevent; public health relevance; receptor; response; small molecule; therapeutic target; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): A major challenge to the prevention or treatment of breast cancer metastasis is to understand how tumors respond to environmental signals that regulate their invasive/migratory capacity and then develop selective therapeutic strategies to abrogate these processes. We have identified a novel pathway (the cell surface receptor tyrosine kinase discoidin domain receptor 2 (DDR2)) turned on in breast cancer cells and activated by tumor environmental signals (fibrillar collagen) that is critical for breast cancer metastasis. DDR2 is present on 70% of human invasive breast tumor cells including all clinical subtypes and also invasive DCIS. Importantly DDR2 is not expressed by normal breast epithelia. We have now identified a group of potent and selective novel small molecules that interact with the extracellular domain (ECD) of DDR2 to inhibit DDR2 binding to, and activation by collagen I. When invasive human breast cancer cell lines that express DDR2 are treated with these molecules the activation of DDR2, cell proliferation, and tumor cell invasion are inhibited. We hypothesize that the RTK, DDR2, is a new target for the treatment of breast cancer metastasis and that novel inhibitors targeting the ECD of DDR2 to prevent its activation will be effective in the prevention and, or treatment of breast cancer metastasis. To test these two hypothesis we shall first determine which DDR2 expressing cells within the tumor (epithelial and, or stroma) are critical for DDR2's action in the regulation of breast cancer metastasis and how. Then determine how our novel small molecules inhibit cellular signaling and cellular functions mediated by DDR2 in tumor cells and cancer associated fibroblasts (CAFs), and whether these molecules synergizes with TK inhibitors of DDR2 (Aim 2). Determine the molecular basis for inhibition of DDR2 activation by these novel molecules by solving the crystal structure of the ECD of DDR2 in a complex with inhibitor and ligand (Aim 3). Finally in Aim 4 we will determine if these novel inhibitors of DDR2 block breast cancer metastasis development and regression of already established metastases in vivo.