NMDA receptors in the diagnosis and treatment of pancreatic cancer

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，每年夺去3万多人的生命。预后差，并且由于转移的可能性或广泛的局部发展，成功的治疗很大程度上依赖于早期发现和手术干预。迫切需要对广泛的疾病提供有效的靶向治疗和成功的治疗监测的方法。我们认为这些方法可以通过NMDA受体的抗体产生。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。该项目的目标是为成功治疗和监测胰腺癌，特别是转移性PA提供新方法。正在测试的假设是，我们针对NMDA受体的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，并允许它们成像。目标是：(i)确定我们一种可用的抗nmdar1单克隆抗体（mADAMN-1）破坏/阻止人PA皮下和腹腔异种移植物生长的能力；（ii）确定mADAMN-1抗体中99mtechneium标记的fab对胸腺小鼠中生长的小而弥散性PA肿瘤的成像效果；（iii）确认NMDAR1和NMDAR2B受体在胰腺癌中的表达分布、丰度和肿瘤选择性。用抗体治疗将与使用普遍存在的IgG进行比较。这些调查将采用抗体管理和治疗肿瘤的每日大小测量。他们还将包括全身扫描成像，用于放射性标签，应该集中在肿瘤上，然后测量不同组织的放射性。亲和层析，人体组织免疫组化，RIA， ELISA, RT-PCR，克隆，DNA测序，Western分析和病理评估也将进行。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。我们相信这个项目将导致产生广泛可用和敏感的方法，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。在治疗期间同时监测转移性癌症的方法也应该即将出现。此外，我们的方法甚至可以为早期癌症检测、转移性和残留肿瘤定位以及复发性疾病评估提供方法。

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.