A Novel Agent with Dual Functions to Treat Head and Neck Cancer

一种具有双重功能的治疗头颈癌的新型药物

• 批准号: 8638361
• 负责人: FREDERICK Gary TOBACK
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638361
• 关键词: Actins; Acute; Adverse effects; Amino Acids; Animal Model; Animals; Antineoplastic Agents; Apoptosis; Apoptotic; Appearance; Atrophic; Binding; Biological; Biological Process; Cancer Cell Growth; Cancer cell line; Cell Fraction; Cell Line; Cells; Chemotherapy-Oncologic Procedure; Chicago; Cholecystokinin; Cholecystokinin B Receptor; Chronic Gastritis; Cisplatin; Clinical Trials; Complication; Cultured Cells; Detergents; Development; Dose; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Exhibits; Exposure to; Face; Gastric mucosa; Goals; Growth; Hamsters; Head and Neck Cancer; Head and Neck Neoplasms; Head and neck structure; Healed; Health; Heat shock proteins; Human; Immunohistochemistry; In Vitro; Injury; Intestinal Metaplasia; Laboratories; Learning; Length; MAP Kinase Gene; MAPK14 gene; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Nude Rats; Oral; Oral cavity; Oral mucous membrane structure; Pain; Pathway interactions; Patients; Peptides; Phosphorylation; Positioning Attribute; Property; Protein Fragment; Protein Kinase C; Proteins; Proto-Oncogene Proteins c-akt; Protocols documentation; Radiation; Radiation Injuries; Radiation therapy; Radio; Radioprotection; Receptor Activation; Receptor Signaling; Recombinants; Recovery; Regimen; Role; Saline; Signal Pathway; Simulate; Speed; Stomach; Structure; Surface; Symptoms; Therapeutic Agents; Therapeutic Effect; Tight Junctions; Tissues; Tongue; Transfection; Translating; Tumor Suppressor Proteins; Tumor Volume; Ulcer; Universities; Xenograft Model; anticancer treatment; cancer cell; cancer therapy; cell growth; chemoradiation; chemotherapy; conventional therapy; cytotoxicity; effective therapy; head and neck cancer patient; healing; human disease; in vivo; injured; insight; malignant stomach neoplasm; mouse model; neoplastic cell; novel; novel therapeutics; oral mucositis; overexpression; prevent; programs; protein function; radiation effect; receptor; recombinant peptide; rho; senescence; subcutaneous; treatment program; tumor

DESCRIPTION (provided by applicant): Oral mucositis (OM) is a common, devastating complication of radiation and chemotherapeutic antineoplastic regimens, particularly in patients with head and neck cancers, for which no effective therapy is currently available. We have identified a 21 amino acid peptide derived from a novel 18-kD Antrum Mucosal Protein (AMP-18) that facilitates healing of injured oral mucosal tissue in two animal models, and increases the efficacy of cisplatin and radiation treatment. Subcutaneous administration of the AMP peptide protected the surface epithelium of mouse tongue against acute radiation injury. Treatment with the peptide also delayed the appearance and reduced the extent of ulcer formation in the buccal mucosa of hamsters exposed to radiation alone, or with cisplatin. AMP-18 functions as a pleiotropic agent in cultured cells and in vivo, exhibits anti- apoptotic, motogenic and mitogenic effects, and protects epithelial barrier function and structure by targeting tight junction proteins. To determine the mechanisms by which AMP-18 and the peptide exerts their effects, we recently identified the cholecystokinin-B/gastrin receptor (CCKBR) as a receptor for AMP-18, and verified its expression in normal human oral mucosal tissue by immunohistochemistry. Binding of AMP-18 to CCKBR activates MAPKs, Rho, Akt and PKC? pathways. The AMP peptide exhibits the same biological functions as does the full-length protein. To find out if treatment of OM with AMP peptide could block the tumorolytic effect of radiation, we created a xenograft model of human cancer cells in nude rats that received radiation with or without AMP peptide. Administration of AMP peptide unexpectedly enhanced radiation-induced growth inhibition without causing any adverse effects in the animals. This tumor suppressor function is supported by observations showing that expression of AMP-18 is downregulated or absent in gastric cancer tissue, and that transfection and overexpression of AMP-18 in gastric cancer cell lines can induce apoptosis or senescence. To develop AMP peptide as a therapeutic agent, we investigated the effects of the peptide on growth of a head and neck cancer cell line, SCC61, in the presence of cisplatin. Treatment with AMP peptide or recombinant human (rh) AMP-18, together with cisplatin, additively reduced cell growth. Thus AMP peptide/rhAMP-18 has dual effects in vitro and in vivo: it protects and facilitates healing of injured oral mucosal tissue, and enhances efficacy of antineoplastic strategies. Specific Aim #1 is to demonstrate in an orthotopic mouse model of squamous cell cancer of the oral tongue, that AMP peptide administered together with radiation exerts both its radioprotective and tumor-suppressing properties in the same animal. Aim #2 is to identify mechanisms by which AMP peptide heals injured oral mucosal tissue, but can also inhibit growth of head and neck cancer cells following exposure to radiation and/or cisplatin. Identification of molecular mechanisms by which AMP peptide exerts its pleiotropic effects could speed its development as a novel therapeutic for OM in patients with head and neck cancers.

描述(申请人提供)：口腔粘膜炎(OM)是放射和化疗抗肿瘤方案的一种常见的破坏性并发症，特别是在头颈部癌症患者中，目前还没有有效的治疗方法。我们已经从一种新的18-kD的胃窦粘膜蛋白(AMP-18)中发现了一种21个氨基酸的多肽，它可以在两个动物模型中促进受损口腔粘膜组织的愈合，并增加顺铂和放射治疗的疗效。皮下注射AMP多肽可保护小鼠舌表面上皮细胞免受急性辐射损伤。用这种多肽治疗也推迟了单独暴露于辐射或顺铂暴露的仓鼠口腔粘膜的出现，并减少了溃疡形成的程度。AMP-18在培养细胞和体内发挥多效性作用，表现出抗凋亡、促运动和促有丝分裂的作用，并通过靶向紧密连接蛋白来保护上皮屏障的功能和结构。为了确定AMP-18及其多肽的作用机制，我们最近鉴定了CCKBR是AMP-18的受体，并用免疫组织化学方法证实了其在正常口腔黏膜组织中的表达。AMP-18与CCKBR结合激活MAPKs、Rho、Akt和PKC？小路。AMP多肽具有与全长蛋白相同的生物学功能。为了了解AMP多肽治疗OM是否能阻断辐射的肿瘤杀伤作用，我们建立了人癌细胞裸鼠移植瘤模型，分别接受或不加AMP多肽的照射。给予AMP多肽意外地增强了辐射诱导的生长抑制，而没有在动物中引起任何不良反应。有观察表明，AMP-18在胃癌组织中的表达下调或缺失，并且AMP-18在胃癌细胞系中的转染和过表达可以诱导细胞凋亡或衰老，这一抑癌功能得到了观察的支持。为了开发AMP多肽作为治疗药物，我们研究了AMP多肽在顺铂存在下对头颈部癌细胞株SCC61生长的影响。用AMP多肽或重组人(Rh)AMP-18与顺铂一起处理，会额外减少细胞的生长。因此，AMP多肽/重组人AMP-18在体外和体内具有双重作用：保护和促进口腔黏膜损伤组织的愈合，并增强抗肿瘤策略的疗效。具体目标#1是在口腔舌鳞状细胞癌的原位小鼠模型上证明，AMP多肽与辐射一起在同一动物中发挥辐射防护和肿瘤抑制特性。目的#2确定AMP肽修复口腔黏膜损伤组织的机制，但也能抑制放射和/或顺铂暴露后的头颈部癌细胞的生长。明确AMP多肽发挥多效性的分子机制，可加速AMP作为治疗头颈癌患者OM的新方法的发展。