Cadherin11 in cancer & rheumatoid arthritis: Common target, common therapies? (5)

钙粘蛋白11在癌症中的作用

• 批准号: 8521213
• 负责人: STEPHEN W BYERS
• 金额: $ 55.09万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521213
• 关键词: Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antineoplastic Agents; Arthritis; Brain Neoplasms; Breast; Breast Cancer Cell; CCL2 gene; Cancer Biology; Cancer Prognosis; Carcinoma; Cell Adhesion Molecules; Cells; Central Nervous System Neoplasms; Clinic; Clinical Trials; Computer Simulation; Computing Methodologies; Crystallization; Data; Disease; Drug Discovery Groups; ERBB2 gene; Epithelium; Event; FDA approved; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Glioblastoma; Growth; Housing; Human; In Vitro; Incidence; Inflammation Mediators; Inflammatory; Ligands; Link; Malignant Neoplasms; Mediating; Mesenchymal; Methods; Molecular; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; PDGFRB gene; Pathway interactions; Pharmaceutical Preparations; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Recombinants; Regulatory Pathway; Rheumatoid Arthritis; Rheumatology; Role; Series; Shapes; Signal Transduction; Signaling Molecule; Structure; Surface Plasmon Resonance; System; TIMP3 gene; Testing; Work; Xenograft procedure; antibody inhibitor; attenuation; cadherin-11; cancer cell; cancer therapy; celecoxib; chemical property; chemokine; effective therapy; human ESR1 protein; humanized monoclonal antibodies; inhibitor/antagonist; malignant breast neoplasm; migration; mortality; novel; outcome forecast; pre-clinical; receptor; screening; small molecule; structural biology; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Basal-like carcinomas comprise 10-15% of the six breast cancer subtypes, and include those that are 'triple negative' (lacking ER-alpha, PR and HER2 expression), denoting clinically poor prognosis with few treatment options. The mesenchymal cell adhesion molecule, cadherin-11 is expressed only in poorly differentiated, highly invasive basal-like cells and is absent in normal breast epithelium and well-differentiated breast cancer cells. Preliminary data shows that cadherin-11 is commonly increased as an early event in a subset of human breast cancers and ductal carcinomas in-situ and is also elevated in CNS tumors and those of the GI system. Unlike HER2 positive breast cancers for which small molecule and antibody treatment is quite effective; there are no targeted therapies for highly aggressive tumors such as basal-like breast cancer and glioblastomas. However, cadherin-11 is a therapeutic target in the inflammatory disease rheumatoid arthritis (RA) and we found that cadherin-11 monoclonal antibodies, humanized versions of which will shortly be in clinical trials for RA, inhibited the growth of aggressive basal-like breast cancer xenografts in mice. Cadherin-11 attenuation also decreased tumorigenesis, proliferation, colony formation and migration of MDA-MB-231 basal-like breast cancer cells and LN229 glioblastoma cells. These data directly demonstrate that cadherin-11 is a bona-fide therapeutic target in inflammatory diseases such as RA and cancer and prompted us to develop small molecule inhibitors that specifically inhibit the growth and migration of cadherin-11 positive cells. We also found that cadherin-11 regulates CCL2 and other inflammatory mediators and growth regulatory pathways in both RA and cancer cells and further indicates that "some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?" as posited in Provocative Question 5. The proposal will combine the activities of the Cancer Biology and Drug Discovery Group that first described the role of cadherin-11 in breast cancer (Byers, Georgetown), the Rheumatology Group that discovered the role of cadherin-11 in this disease (Brenner, Harvard) and the Structural Biology Group that first determined the crystal structure of cadherin-11 (Shapiro, Columbia). Together we have the following aims. 1. To reposition approved drugs as cadherin-11 inhibitors. Preliminary in silico repositioning identified the anti- inflammatory drug, celecoxib as a cadherin-11 inhibitor. 2. Determine the role of CCL2 and other cadherin-11 regulated genes in mediating its effects on tumorigenesis, invasion and metastasis. 3. Determine the role of tyrosine kinase activation in mediating cadherin-11 signaling.

描述（由申请人提供）：基底样癌占六种乳腺癌亚型的 10-15%，并且包括“三阴性”（缺乏 ER-α、PR 和 HER2 表达）的亚型，表明临床预后不良，治疗选择很少。间充质细胞粘附分子钙粘蛋白-11仅在分化差、高度侵袭性的基底样细胞中表达，在正常乳腺上皮和分化良好的乳腺癌细胞中不表达。初步数据显示，钙粘蛋白 11 通常在人类乳腺癌和原位导管癌的早期事件中升高，并且在中枢神经系统肿瘤和胃肠道系统肿瘤中也升高。与 HER2 阳性乳腺癌不同，小分子和抗体治疗相当有效；对于基底细胞样乳腺癌和胶质母细胞瘤等高度侵袭性肿瘤，尚无靶向治疗方法。然而，cadherin-11 是炎症性疾病类风湿性关节炎 (RA) 的治疗靶点，我们发现 cadherin-11 单克隆抗体（其人源化版本很快将进入 RA 的临床试验）可抑制小鼠中侵袭性基底样乳腺癌异种移植物的生长。 Cadherin-11 减弱还减少了 MDA-MB-231 基底样乳腺癌细胞和 LN229 胶质母细胞瘤细胞的肿瘤发生、增殖、集落形成和迁移。这些数据直接证明cadherin-11是RA和癌症等炎症性疾病的真正治疗靶点，并促使我们开发特异性抑制cadherin-11阳性细胞生长和迁移的小分子抑制剂。我们还发现，cadherin-11 调节 RA 和癌细胞中的 CCL2 和其他炎症介质以及生长调节途径，并进一步表明“一些常用于其他适应症的药物，例如抗炎药，可以预防癌症的发生和死亡，我们能否确定这些药物的作用机制？”如挑衅性问题 5 中提出的。该提案将结合以下机构的活动：首先描述了 cadherin-11 在乳腺癌中的作用的癌症生物学和药物发现小组（Byers，乔治城）、发现了 cadherin-11 在这种疾病中的作用的风湿病学小组（哈佛大学的布伦纳）以及首先确定了 cadherin-11 晶体结构的结构生物学小组（哥伦比亚的 Shapiro）。我们共同实现以下目标。 1. 将已批准的药物重新定位为钙粘蛋白-11抑制剂。初步计算机重新定位确定抗炎药塞来昔布为钙粘蛋白 11 抑制剂。 2.确定CCL2和其他cadherin-11调节基因在介导其对肿瘤发生、侵袭和转移的影响中的作用。 3. 确定酪氨酸激酶激活在介导钙粘蛋白-11 信号传导中的作用。