NMDA receptors in the diagnosis and treatment of pancreatic cancer

描述(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，而且由于转移潜能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。迫切需要对广泛疾病提供有效的靶向治疗和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癌(PA)的高表达特征，并且可以安全地被识别细胞外区域独特序列的抗体靶向。受体促进PA的生长，但受体拮抗剂和抗体可以抑制PA的生长。因此，这些受体的表达不仅为我们提供了开发新的辅助治疗的机会，而且还为监测疾病的治疗提供了机会。本项目的目的是为成功治疗和监测胰腺癌，特别是转移性PA提供新的方法。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试剂，防止人PA异种移植的生长，并允许对其进行成像。目标针对：(I)确定我们现有的一种抗NMDAR1单抗(mADAMN-1)的能力，以摧毁/防止人PA皮下和腹膜内移植瘤的生长；(Ii)确定从mADAMN-1抗体中标记的99mTechneb对作为实验动物的裸鼠体内生长的细小且播散性的PA肿瘤进行成像的有效性；以及(Iii)证实NMDAR1和NMDAR2B受体在胰腺癌中的分布、丰度和肿瘤选择性表达。使用抗体的治疗将与使用无处不在的免疫球蛋白的治疗进行比较。这些研究将使用抗体注射和治疗后肿瘤的每日大小测量。此外，它们还将涉及全身扫描成像，以确定应该集中在肿瘤中的放射性标记，以及稍后测量不同组织中的放射性。还将进行亲和层析、人体组织免疫组化、放射免疫分析、酶联免疫吸附试验、RT-PCR、克隆和DNA测序、蛋白质分析和病理学评估。影像、IHC和病理学的解释将受益于放射科医生艾伦·西格尔、病理学家文斯·梅莫利和胰腺肿瘤学家蒂姆·加德纳的专业知识。我们相信，这个项目将带来广泛可用的敏感方法的产生，有可能更有效地治疗大多数晚期和复发的胰腺癌患者。在治疗过程中同时监测转移性癌症的方法也应该出现。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疾病评估的方法。

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.