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

基本信息

批准号：
9330122
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
项目类别：
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/9330122
关键词：
Architecture Basic Science Binding Binding Sites Biology Blood Vessels Breast Cancer Cell Breast Cancer Prevention 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 Crystallization DDR1 gene Data Development Dimerization Disease Drug Targeting Duct (organ) structure Ductal Environment Epithelial Extracellular Domain Extracellular Structure Fibrillar Collagen Fibroblasts Genetic Growth Factor Human In Vitro Integrins Investigation Kinetics Ligand Binding Ligands Lymphatic Malignant Neoplasms Mammary Neoplasms Mediating Molecular Molecular Conformation 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 dimer discoidin domain receptor 2 effective therapy extracellular humanized antibody in vivo inhibitor/antagonist interstitial malignant breast neoplasm mammary epithelium migration neoplastic cell novel novel therapeutics organ growth prevent public health relevance receptor response small molecule small molecule inhibitor therapeutic target tumor tumor microenvironment tumor progression

项目摘要

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.

描述（由适用提供）：预防或治疗乳腺癌转移的主要挑战是了解肿瘤如何对调节其侵入性/迁徙能力的环境信号反应，然后制定选择性的治疗策略来消除这些过程。我们已经确定了一种新的途径（细胞表面受体酪氨酸激酶盘状结构域受体2（DDR2））在乳腺癌细胞中打开，并被肿瘤环境信号（Fibrillar胶原蛋白）激活，这对乳腺癌转移至关重要。 DDR2存在于70％的人类浸润性乳腺肿瘤细胞中，包括所有临床亚型和浸润性DCI。重要的是，DDR2不受正常乳腺上皮的表达。现在，我们已经确定了与DDR2的细胞外结构域（ECD）相互作用的一组潜在的和选择性的小分子，以抑制DDR2与胶原蛋白I的结合，并激活胶原蛋白I。当与这些分子的DDR2激活DDR2的激活，细胞扩增和Tumor celliss Indiss Ins Ins Ins Ins Ins Ins Ins Ins Ins Ins in n ins collage ddr2时。我们假设RTK DDR2是治疗乳腺癌转移的新靶标，并且针对DDR2 ECD以防止其激活的新型抑制剂将有效预防和或治疗乳腺癌转移。为了检验这两个假设，我们将首先确定肿瘤内哪些DDR2表达细胞（上皮和或基质）对于DDR2在调节乳腺癌转移中的作用至关重要。然后确定我们的新型小分子如何抑制肿瘤细胞中DDR2介导的细胞信号传导和细胞功能，以及癌症相关的成纤维细胞（CAF），以及这些分子是否与DDR2的TK抑制剂合成（AIM 2）。通过在与抑制剂和配体的复合物中求解DDR2的ECD的晶体结构来确定这些新分子抑制DDR2激活的分子基础（AIM 3）。最后，在AIM 4中，我们将确定这些新型DDR2的抑制剂是否阻断了乳腺癌转移的发展和体内已建立的转移酶的回归。