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: 9768974
• 负责人: Gregory D. Longmore
• 金额: $ 33.84万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768974
• 关键词: Architecture; Basic Science; Binding; Binding Sites; Biological; 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; breast cancer progression; clinical subtypes; cytokine; 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; protein structure; public health relevance; receptor; response; small molecule; small molecule inhibitor; 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.

 描述（由申请人提供）：预防或治疗乳腺癌转移的一个主要挑战是了解肿瘤如何对调节其侵袭/迁移能力的环境信号作出反应，然后开发选择性治疗策略以消除这些过程。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（纤维胶原）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上，包括所有临床亚型和浸润性DCIS。重要的是，正常乳腺上皮细胞不表达DDR2。我们现在已经鉴定了一组有效的和选择性的新型小分子，其与DDR2的胞外结构域（ECD）相互作用以抑制DDR2与胶原I的结合和激活。当用这些分子处理表达DDR2的侵袭性人乳腺癌细胞系时，DDR2的活化、细胞增殖和肿瘤细胞侵袭被抑制。 我们假设RTK，DDR2，是治疗乳腺癌转移的新靶点，并且靶向DDR2的ECD以防止其活化的新型抑制剂将有效地预防和/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（上皮和/或间质）内的哪些DDR2表达细胞对于DDR2在乳腺癌转移的调节中的作用是关键的以及如何关键。然后确定我们的新型小分子如何抑制肿瘤细胞和癌症相关成纤维细胞（CAF）中DDR2介导的细胞信号传导和细胞功能，以及这些分子是否与DDR2的TK抑制剂协同作用（Aim 2）。通过解析具有抑制剂和配体的复合物中DDR2的ECD的晶体结构，确定这些新型分子抑制DDR2活化的分子基础（目的3）。最后，在目标4中，我们将确定这些新型DDR2抑制剂是否在体内阻断乳腺癌转移的发展和已经建立的转移的消退。

项目成果

Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain.

• DOI: 10.1073/pnas.1805020115
• 发表时间: 2018-08-14
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Grither WR;Longmore GD
• 通讯作者: Longmore GD