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，特别是胰腺腺癌，是美国第四大最常见的癌症死亡原因，每年夺走超过 30,000 人的生命。预后很差，而且由于转移潜力或广泛的局部发展很高，成功的治疗在很大程度上依赖于早期发现和手术干预。迫切需要能够对广泛疾病提供有效靶向治疗并成功监测治疗的方法。我们认为这些方法可以通过 NMDA 受体抗体产生。我们的数据显示 NMDA 受体可能是所有或大多数胰腺腺癌 (PA) 的高表达特征，并且可以被识别细胞外结构域独特序列的抗体安全地靶向。受体促进 PA 的生长，而 PA 的生长可被受体拮抗剂和抗体抑制。因此，此类受体的表达不仅为我们提供了开发新辅助疗法的机会，而且还为监测疾病的治疗提供了机会。该项目的目的是提供成功治疗和监测胰腺癌，特别是转移性 PA 的新方法。正在测试的假设是，我们的 NMDA 受体抗体将作为有效的靶向剂来阻止人类 PA 异种移植物的生长，并允许它们进行成像。目标针对：(i) 确定我们现有的一种抗 NMDAR1 单克隆抗体 (mADAMN-1) 破坏/阻止人 PA 皮下和腹膜内异种移植物生长的能力； (ii) 确定来自 mADAMN-1 抗体的 99m 锝标记的 Fab 对作为测试动物的无胸腺小鼠中生长的小型和播散性 PA 肿瘤进行成像的有效性； (iii) 确认 NMDAR1 和 NMDAR2B 受体在胰腺癌中表达的分布、丰度和肿瘤选择性。使用抗体的治疗将与使用普遍存在的 IgG 的治疗进行比较。这些研究将采用抗体给药和每日测量治疗肿瘤的大小。他们还将涉及全身扫描成像，以获取应集中在肿瘤中的放射性标记，以及随后测量不同组织中的放射性。还将进行亲和层析、人体组织 IHC、RIA、ELISA、RT-PCR、克隆和 DNA 测序、Western 分析和病理学评估。影像学、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 和胰腺肿瘤学家 Tim Gardner 的专业知识。我们相信这个项目将导致产生广泛可用且敏感的方法，有可能更有效地治疗大多数患有晚期和复发性胰腺癌的个体。在治疗过程中同时监测转移性癌症的方法也应该随之出现。此外，我们的方法甚至可以带来早期癌症检测、转移性和残留肿瘤定位以及复发性疾病评估的方法。