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: 8706096
• 负责人: STEPHEN W BYERS
• 金额: $ 56.6万
• 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/8706096
• 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; MDA MB 231; 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％，其中包括“三重阴性”（缺乏ER-Alpha，PR和HER2表达）的癌，表示临床上较差的预后，而治疗方案很少。间充质细胞粘附分子，cadherin-11仅在分化较差的高度浸润性基底样细胞中表达，并且在正常的乳房上皮和良好分化的乳腺癌细胞中不存在。初步数据表明，在人类乳腺癌和原位导管癌中，Cadherin-11通常是早期事件，并且在中枢神经系统肿瘤和GI系统中也升高。与HER2阳性乳腺癌不同，小分子和抗体治疗非常有效。没有针对高度侵袭性肿瘤的靶向疗法，例如基底样乳腺癌和胶质母细胞瘤。然而，钙粘蛋白-11是炎症性疾病类风湿关节炎（RA）的治疗靶标，我们发现cadherin-111单克隆抗体，其人性化版本将在RA的临床试验中进行RA，抑制侵袭性基础类乳腺癌的生长。 Cadherin-11衰减还减少了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，菌落形成和迁移。这些数据直接表明Cadherin-11是RA和癌症等炎症性疾病中的真正的治疗靶标，并促使我们开发出小分子抑制剂，该抑制剂专门抑制了Cadherin-11阳性细胞的生长和迁移。我们还发现，Cadherin-11调节RA和癌细胞中的CCL2和其他炎症介质和生长调节途径，进一步表明“某些药物通常用于其他适应症的药物，例如抗炎药，例如抗炎药，例如保护癌症的发生和死亡率，我们可以通过这些药物来确定这些药物的机制？”正如挑衅性问题5所述。该提案将结合癌症生物学和药物发现小组的活动，该小组首先描述了钙粘蛋白11在乳腺癌中的作用（Byers，Georgetown），这是结构性生物学组（Brenner，Harvard）和结构生物学组的结构性结构，该组发现了Cadherin-111的作用，该疾病（Brenner，Hardner，Harthard）确定了Crybia-Crybia-11（Shapherin）。我们共同有以下目标。 1。将批准的药物重新定位为Cadherin-11抑制剂。在硅硅的初步重新定位，将抗炎性药物塞来氧化鉴定为cadherin-11抑制剂。 2。确定CCL2和其他Cadherin-11的作用在介导其对肿瘤发生，侵袭和转移的影响中的作用。 3。确定酪氨酸激酶活化在介导钙蛋白11信号传导中的作用。