The objective of this research proposal is the development and evaluation of immunoassays having clinical utility for the "early" detection and diagnosis of pancreatic carcinoma. In the year 2009, an estimated 42,000 new cases of pancreatic carcinoma will be diagnosed in the United States. Pancreatic carcinoma is the tenth most common form of cancer in men and women today, yet it is the fourth leading cause of cancer deaths. The most common symptoms of the disease, jaundice, abdominal pain, and weight loss, together with other presenting factors are nonspecific in nature. Thus, diagnosing pancreatic carcinoma at an early stage of tumor growth is difficult at best, requiring considerable suspicion and extensive diagnostic work-up, up to and including exploratory surgery. Our laboratory has developed and characterized the PAM4 monoclonal antibody (murine, chimeric and humanized versions), providing evidence as to its potential for clinical detection, imaging and therapy of pancreatic carcinoma. Our recent developments employing an in vitro enzyme immunoassay to quantitate PAM4-reactive antigen in the blood of patients, appears quite promising for detection of pancreatic carcinoma and its discrimination from pancreatitis, as well as other cancers and normal individuals. Early detection and diagnosis of pancreatic carcinoma, as well as appropriate staging of the disease, would almost certainly provide a survival advantage. With this in mind, we intend to further develop and assess the ability of the PAM4-based immunoassays, both immunohistochemical detection in tissue specimens and enzyme immunoassay to detect and quantitate the antigen in both serum and pancreatic fluids, to provide "early" detection and diagnosis at a time-point when therapeutic intervention may have better opportunity for successful outcome.
The specific aims of this project are: 1. To evaluate the performance profile of the PAM4-Immunoassay for diagnostic accuracy;2. To evaluate the clinical utility of the PAM4-Immunoassay for a-accurate diagnosis of patients presenting with symptoms suggestive of pancreatic cancer;b- early detection of pancreatic carcinoma in asymptomatic individuals at high risk for pancreatic cancer;c- assessment of tumor response or early detection of relapse;3. To evaluate the nature of the antigen to which PAM4 is reactive.
Pancreatic carcinoma is an insidious disease with a particularly high mortality rate. In large measure, this is due to the location of the tumor where it can grow in a silent fashion. Symptoms that might suggest the patient seek medical assistance are usually not evident until an advanced stage of tumor growth. Compounding this challenge is that currently available treatment procedures have not been able to provide a cure for the overwhelming majority of patients. Our goal is to provide an antibody approach for early detection and diagnosis of the disease at a time when curative procedures have a better opportunity for successful outcome. We have developed monoclonal antibody PAM4 that has a high specificity for pancreatic carcinoma as compared to benign pancreatic disease, other types of malignancies, and normal individuals. Thus, the detection of the PAM4-reactive antigen provides a high likelihood for the diagnosis of pancreatic cancer.
The aims of the proposed research are to further define the specificity of the antibody as to its ability to provide accurate diagnoses, and to examine the value of the immunoassay for "early" detection of pancreatic carcinoma, prior to the development of symptoms, in a group of patients considered to be at high risk for development of the disease.
|Liu, Donglin; Chang, Chien-Hsing; Gold, David V et al. (2015) Identification of PAM4 (clivatuzumab)-reactive epitope on MUC5AC: a promising biomarker and therapeutic target for pancreatic cancer. Oncotarget 6:4274-85|
|Shi, Chanjuan; Merchant, Nipun; Newsome, Guy et al. (2014) Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry. Arch Pathol Lab Med 138:220-8|
|Gold, David V; Gaedcke, Jochen; Ghadimi, B Michael et al. (2013) PAM4 enzyme immunoassay alone and in combination with CA 19-9 for the detection of pancreatic adenocarcinoma. Cancer 119:522-8|
|Sopha, Sabrina C; Gopal, Purva; Merchant, Nipun B et al. (2013) Diagnostic and therapeutic implications of a novel immunohistochemical panel detecting duodenal mucosal invasion by pancreatic ductal adenocarcinoma. Int J Clin Exp Pathol 6:2476-86|
|Gold, David V; Newsome, Guy; Liu, Donglin et al. (2013) Mapping PAM4 (clivatuzumab), a monoclonal antibody in clinical trials for early detection and therapy of pancreatic ductal adenocarcinoma, to MUC5AC mucin. Mol Cancer 12:143|
|Ocean, Allyson J; Pennington, Kenneth L; Guarino, Michael J et al. (2012) Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial. Cancer 118:5497-506|
|Gulec, Seza A; Cohen, Steven J; Pennington, Kenneth L et al. (2011) Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial. Clin Cancer Res 17:4091-100|
|Gold, David V; Stein, Rhona; Burton, Jack et al. (2010) Enhanced expression of CD74 in gastrointestinal cancers and benign tissues. Int J Clin Exp Pathol 4:1-12|
|Gold, David V; Goggins, Michael; Modrak, David E et al. (2010) Detection of early-stage pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 19:2786-94|
|Modrak, David E; Leon, Evelyn; Goldenberg, David M et al. (2009) Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol Cancer Res 7:890-6|
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