NMDA receptors in the diagnosis and treatment of pancreatic cancer

NMDA受体在胰腺癌诊断和治疗中的作用

基本信息

批准号：
8445025
负责人：
WILLIAM G NORTH
金额：
$ 17.62万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445025
关键词：
Accounting Address Adenocarcinoma Adjuvant Adjuvant Chemotherapy Adjuvant Therapy Affinity Chromatography Alcohol or Other Drugs use Animal Testing Animals Antibodies Apoptotic Behavior Biopsy Blinded Blocking Antibodies Brain CA-19-9 Antigen Cancer Etiology Cause of Death Cell membrane Cells Cessation of life Clinical Cloning Computer software Coupling Cystic Fibrosis DNA Sequence Data Development Diagnosis Disease Disseminated Malignant Neoplasm Dose Early Diagnosis Effectiveness Elements Enzyme-Linked Immunosorbent Assay Evaluation Excision Extracellular Domain Fab Immunoglobulins Fc Receptor Gamma Cameras Generations Goals Growth Heterogeneity Human IgG1 Image Immunoglobulin G In Vitro Individual Investigation Label Lead Legal patent Location Malignant Neoplasms Malignant neoplasm of pancreas Measurement Metastatic Pancreatic Adenocarcinoma Methods Monitor Monoclonal Antibodies Mus N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neoplasm Metastasis Normal tissue morphology Nude Mice Oncologist Operative Surgical Procedures Organ Outcome Pancreas Pancreatic Adenocarcinoma Pancreatitis Pathologist Pathology Patients Pentetic Acid Persons Pilot Projects Procedures Radiation therapy Radioactivity Radiolabeled Recurrence Recurrent disease Residual Tumors Reverse Transcriptase Polymerase Chain Reaction Screening for cancer Spinal Staging Staining method Stains Survival Rate Testing Tissues Tumor Burden Tumor Tissue Weight Widespread Disease Xenograft procedure cell growth effective therapy follow-up human monoclonal antibodies human tissue improved in vivo intraperitoneal killings minimally invasive monoclonal antibody MOPC21 mouse model neoplastic cell outcome forecast pancreatic cancer cells pancreatic neoplasm prevent public health relevance radiologist radiotracer receptor subcutaneous success successful intervention tumor uptake whole body imaging/scanning

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer, particularly adenocarcinoma of the pancreas, is the fourth most common cause of cancer death in the US, accounting for than 30,000 lives each year. Prognosis is poor, and because metastatic potential, or extensive local development, is high, successful treatment relies heavily on early detection and surgical intervention. There is a critical need for methods that provide effective targeted treatment of extensive disease and successful monitoring of therapy. We are of the opinion that these methods could be generated through antibodies to NMDA receptors. Our data show NMDA receptors are likely highly expressed features of all or most pancreatic adenocarcinomas (PA), and can be safely targeted by antibodies recognizing unique sequences of extracellular domains. The receptors promote growth of PA that can be inhibited by receptor antagonists and antibodies. Expression of such receptors therefore not only presents us with the opportunity to develop new adjuvant therapies but also to monitor treatment of the disease The objective of this project is to provide new methods for successfully treating and monitoring pancreatic cancer, particularly metastatic PA. The hypothesis being tested is that our antibodies to NMDA receptors will serve as effective targeting agents to prevent growth of human PA xenografts, and allow them to be imaged. Goals are directed towards: (i) determining the ability of one of our available anti-NMDAR1 monoclonal antibodies (mADAMN-1) to destroy/prevent growth of human PA subcutaneous, and intraperitoneal, xenografts; (ii) ascertaining the effectiveness of 99mTechnetium-labeled Fabs from mADAMN-1 antibody to image small and disseminated PA tumors grown in athymic mice as test animals; and (iii) confirming the distribution, abundance, and tumor selectivity of expression in pancreatic cancer of both NMDAR1 and NMDAR2B receptors . Treatment with antibodies will be compared with those using ubiquitous IgG. These investigations will employ antibody administration and daily size measurements of treated tumors. They will additionally involve whole body scan imaging for radiolabel that should be concentrated in the tumors, and later measurement of radioactivity in different tissues. Affinity chromatography, IHC of human tissues, RIA, ELISA, RT-PCR, cloning, and DNA sequencing, Western analysis, and pathology assessments will also be performed. Interpretation of imaging, IHC, and pathology will benefit from the expertise of radiologist Alan Siegel, pathologist Vince Memoli and pancreatic oncologist Tim Gardner. We believe this project will lead to the generation of widely available and sensitive methods with the potential to more effectively treat most individuals suffering from late stage and recurrent pancreatic cancer. Methods that concurrently monitor metastatic cancer during therapy should also be forthcoming. Additionally, our approach could even lead to methods for early cancer detection, for metastatic and residual tumor localization, and for recurrent disease assessment.

描述（由申请人提供）：胰腺癌，尤其是胰腺腺癌，是美国癌症死亡的第四个最常见原因，每年占30,000多人的生命。预后很差，并且由于转移性潜力或广泛的局部发展，成功的治疗方法在很大程度上取决于早期发现和手术干预。对于提供有效靶向广泛疾病和成功监测治疗的方法的方法迫切需要。我们认为可以通过对NMDA受体的抗体生成这些方法。我们的数据表明，NMDA受体可能是所有或大多数胰腺腺癌（PA）的高度表达特征，并且可以通过识别识别独特细胞外域序列的抗体安全地靶向。受体促进受体拮抗剂和抗体可以抑制PA的生长。因此，这种受体的表达不仅为我们提供了开发新辅助疗法的机会，而且还监测该疾病的治疗，该项目的目的是提供成功治疗和监测胰腺癌的新方法，尤其是转移性PA。测试的假设是，我们对NMDA受体的抗体将作为防止人PA异种移植物生长的有效靶向剂，并允许它们成像。目标是针对以下方面的：（i）确定我们可用的抗NMDAR1单克隆抗体（Madamn-1）的能力，以破坏/防止人PA皮下的生长和腹膜内的异种移植物的能力；（ii）确定从女士1抗体到图像小鼠中小鼠中生长的小型PA肿瘤的99mtechnetium标记的晶圆厂的有效性；（iii）确认NMDAR1和NMDAR2B受体的胰腺癌表达的分布，丰度和肿瘤选择性。将抗体治疗将与使用无处不在的IgG进行比较。这些研究将采用治疗肿瘤的抗体给药和每日测量。它们还将涉及应集中在肿瘤中的放射性标记的全身扫描成像，然后在不同组织中测量放射性。还将进行亲和色谱，人体组织的IHC，RIA，ELISA，RT-PCR，克隆和DNA测序，西方分析和病理评估。对成像，IHC和病理学的解释将受益于放射科医生Alan Siegel，病理学家Vince Memoli和Pancreatic肿瘤学家Tim Gardner的专业知识。我们认为，该项目将导致广泛获得和敏感的方法产生，并有可能更有效地治疗大多数患有晚期和经常性胰腺癌的人。在治疗期间同时监测转移性癌症的方法也应即将进行。此外，我们的方法甚至可能导致早期癌症检测，转移性和残留肿瘤定位以及反复疾病评估的方法。