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

• 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
• 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

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，是美国癌症死亡的第四大常见原因，每年导致30，000多人死亡。预后很差，并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。迫切需要提供广泛疾病的有效靶向治疗和治疗的成功监测的方法。我们认为，这些方法可以通过抗体产生的NMDA受体。我们的数据显示，NMDA受体可能是所有或大多数胰腺癌（PA）的高表达特征，并且可以被识别细胞外结构域的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，这些受体的表达不仅为我们提供了开发新的辅助疗法的机会，而且还为监测疾病的治疗提供了机会。本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，以防止人类PA异种移植物的生长，并允许他们成像。目标是：（i）确定我们的一种可用的抗NMDAR 1单克隆抗体（ii）确定来自mADAMN-1抗体的99 m锝标记的Fab对在作为测试动物的无胸腺小鼠中生长的小的和播散的PA肿瘤成像的有效性;和（iii）证实NMDAR 1和NMDAR 2B受体在胰腺癌中表达的分布、丰度和肿瘤选择性。将抗体治疗与使用普遍存在的IgG治疗进行比较。 这些研究将采用抗体给药和治疗肿瘤的每日大小测量。它们还将涉及全身扫描成像，用于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、免疫组化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。 我们相信该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晚期和复发性胰腺癌患者。在治疗期间同时监测转移性癌症的方法也应该即将到来。此外，我们的方法甚至可能导致早期癌症检测，转移和残留肿瘤定位以及复发性疾病评估的方法。