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: 8384229
• 负责人: STEPHEN W BYERS
• 金额: $ 61.53万
• 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/8384229
• 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Basal-like breast cancers and brain tumors of the glioblastoma type are among the poorest prognosis cancers with no effective treatments. This proposal links a molecular pathway elevated in these tumors to a similar pathway important in the inflammatory disease rheumatoid arthritis. We propose that drugs currently in use for arthritis as well as drugs repurposed to inhibit the common pathway will be useful as novel cancer therapies.

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HER 2表达）的那些，表示临床预后不良，治疗选择很少。间充质细胞粘附分子钙粘蛋白-11仅在低分化、高侵袭性基底样细胞中表达，在正常乳腺上皮和高分化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导管原位癌的一个子集中作为早期事件增加，并且在CNS肿瘤和GI系统肿瘤中也升高。与小分子和抗体治疗非常有效的HER 2阳性乳腺癌不同，对于高侵袭性肿瘤（如基底样乳腺癌和胶质母细胞瘤）没有靶向治疗。然而，钙粘蛋白-11是炎症性疾病类风湿性关节炎（RA）的治疗靶点，我们发现钙粘蛋白-11单克隆抗体，其人源化版本将很快在RA的临床试验中，抑制小鼠中侵袭性基底样乳腺癌异种移植物的生长。钙粘蛋白-11衰减还降低了MDA-MB-231基底样乳腺癌细胞和LN 229胶质母细胞瘤细胞的肿瘤发生、增殖、集落形成和迁移。这些数据直接表明钙粘蛋白-11是炎症性疾病如RA和癌症的真正治疗靶点，并促使我们开发特异性抑制钙粘蛋白-11阳性细胞生长和迁移的小分子抑制剂。我们还发现钙粘蛋白-11调节CCL 2和其他炎症介质以及RA和癌细胞中的生长调节途径，并进一步表明“一些常用于其他适应症的药物，如抗炎药，可以预防癌症的发病率和死亡率，我们能否确定这些药物的作用机制？“正如挑衅性问题5中所提出的。该提案将联合收割机的活动，癌症生物学和药物发现组，首先描述了钙粘蛋白-11在乳腺癌中的作用（拜尔斯，乔治敦），流变学组，发现钙粘蛋白-11在这种疾病中的作用（布伦纳，哈佛）和结构生物学组，首先确定钙粘蛋白-11的晶体结构（夏皮罗，哥伦比亚）。我们一起有以下目标。1.将批准的药物重新定位为钙粘蛋白-11抑制剂。初步的计算机重新定位确定抗炎药物塞来昔布是钙粘蛋白-11抑制剂。2.确定CCL 2和其他钙粘蛋白-11调节基因在介导其对肿瘤发生、侵袭和转移的作用中的作用。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。 公共卫生相关性：基底样乳腺癌和胶质母细胞瘤型脑肿瘤是预后最差的癌症之一，没有有效的治疗方法。这一提议将这些肿瘤中升高的分子途径与炎性疾病类风湿性关节炎中重要的类似途径联系起来。我们认为，目前用于关节炎的药物以及重新用于抑制共同途径的药物将作为新型癌症疗法。