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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：
8777091
负责人：
FREDERICK Gary TOBACK
金额：
$ 17.18万
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/8777091
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 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 pleiotropism 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）是放疗和化疗方案的一种常见的破坏性并发症，特别是在头颈癌患者中，目前尚无有效的治疗方法。我们已经确定了一种21个氨基酸的肽，来自一种新的18-kD的胃窦粘液蛋白（AMP-18），促进愈合的两个动物模型中受伤的口腔粘膜组织，并增加顺铂和放射治疗的疗效。AMP肽的皮下给药保护小鼠舌表面上皮免受急性辐射损伤。用肽处理还延迟了暴露于单独辐射或顺铂的仓鼠颊粘膜中溃疡形成的出现并降低了溃疡形成的程度。AMP-18在培养的细胞和体内作为多效性剂发挥作用，表现出抗凋亡、促运动和促有丝分裂作用，并通过靶向紧密连接蛋白来保护上皮屏障功能和结构。为了确定AMP-18和肽发挥作用的机制，我们最近确定了胆囊收缩素-B/胃泌素受体（CCKBR）作为AMP-18的受体，并通过免疫组织化学验证了其在正常人口腔粘膜组织中的表达。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。为了发现用AMP肽处理OM是否可以阻断辐射的肿瘤溶解作用，我们在接受有或没有AMP肽的辐射的裸大鼠中建立了人癌细胞的异种移植模型。AMP肽的给药出乎意料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。这种肿瘤抑制功能得到了以下观察结果的支持，即AMP-18的表达在胃癌组织中下调或缺失，并且AMP-18在胃癌细胞系中的转染和过表达可以诱导凋亡或衰老。为了开发AMP肽作为治疗剂，我们研究了在顺铂存在下肽对头颈癌细胞系SCC 61生长的影响。用AMP肽或重组人（rh）AMP-18与顺铂一起处理，相加地降低了细胞生长。因此，AMP肽/rhAMP-18在体外和体内具有双重作用：它保护和促进损伤的口腔粘膜组织的愈合，并增强治疗策略的功效。具体目的#1是在口腔舌鳞状细胞癌的原位小鼠模型中证明，AMP肽与放射一起施用在同一动物中发挥其放射防护和肿瘤抑制特性。目的#2是确定AMP肽愈合受损口腔粘膜组织的机制，但也可以抑制暴露于辐射和/或顺铂后头颈癌细胞的生长。AMP肽发挥其多效性作用的分子机制的鉴定可以加速其作为头颈癌患者OM的新治疗方法的发展。