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.

Public Health Relevance

Our project focuses on two receptor proteins as markers of aggressive pancreatic cancer. Of particular significance, it is expected to lead to effective new targeted treatments for most patients with advanced pancreatic cancer. Such new treatments can then be directly and closely monitored for efficacy by visualizing the receptor protein marker on the tumor. Pancreatic cancer is the fourth leading cause of death from cancer and, for the USA, 37,000 persons died from this disease in 2010. Although there have been many recent advances for effectively treating this disease, prognosis generally is poor, especially for late stage disease, and successful intervention still relies heavily on early detection and surgical removal. There exists a pressing need for precise methods of evaluating changes in tumor burden/location and, for new methods of targeting treatment that are effective in terms of providing long-term survival for patients. We believe the receptor proteins of this project could be the essential elements to achieve these goals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA167329-01A1
Application #
8445025
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$176,175
Indirect Cost
$67,425
Name
Dartmouth College
Department
Physiology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755