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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：口腔粘膜炎（OM）是辐射和化学治疗性抗肿瘤方案的常见并发症，尤其是在头颈癌患者中，目前没有有效的治疗。我们已经确定了一种源自新型的18 kd抗粘膜蛋白（AMP-18）的21个氨基酸肽，该蛋白（AMP-18）促进了两种动物模型中受伤的口服粘膜组织的愈合，并提高了顺铂和放射治疗的疗效。 AMP肽的皮下给药保护了小鼠舌头的表面上皮，免受急性辐射损伤。用肽的治疗还延迟了外观，并降低了单独暴露于辐射或顺铂的仓鼠颊粘膜中溃疡形成程度。 AMP-18在培养细胞和体内充当多效剂，表现出抗凋亡，动作源和有丝分裂作用，并通过靶向紧密的连接蛋白来保护上皮屏障功能和结构。为了确定AMP-18和肽施加其作用的机制，我们最近确定了胆囊基蛋白-B/胃蛋白酶受体（CCKBR）作为AMP-18的受体，并通过免疫组织验证了其在正常人类口服粘膜组织中的表达。 AMP-18与CCKBR的结合激活MAPK，RHO，AKT和PKC？途径。 AMP肽表现出与全长蛋白相同的生物学功能。为了找出用AMP肽对OM的处理是否可以阻止辐射的肿瘤效应，我们在接受或没有AMP肽的辐射的裸鼠中创建了人类癌细胞的异种移植模型。给予AMP肽的给药意外增强的辐射诱导的抑制作用而不会引起动物的任何不良影响。观察结果表明，AMP-18的表达被下调或在胃癌组织中不存在，并且在胃癌细胞系中AMP-18的转染和过表达可以诱导凋亡或衰老。为了发展为治疗剂的AMP肽，我们研究了肽在顺铂存在下的头颈癌细胞系SCC61的生长的影响。用AMP肽或重组人（RH）AMP-18与顺铂一起处理，可添加降低细胞生长。因此，AMP肽/RHAMP-18在体外和体内具有双重影响：它可以保护和促进受伤的口服粘膜组织的愈合，并增强抗塑性策略的功效。具体目的1是在口腔舌的鳞状细胞癌的原位小鼠模型中证明，该模型与放射线一起施用的AMP肽同时在同一动物中施加其放射保护性和肿瘤抑制特性。目的＃2是确定AMP肽可愈合受伤的口服粘膜组织的机制，但在暴露于放射线和/或顺铂后也可以抑制头颈癌细胞的生长。鉴定AMP肽施加其多效性作用的分子机制可以加快其作为头颈癌患者的OM的新型治疗性的发育。