Detection and Diagnosis of Pancreatic Carcinoma

描述(申请人提供)：这项研究计划的目标是开发和评估具有临床实用价值的免疫分析方法，以“早期”发现和诊断胰腺癌。据估计，2009年美国将新增42,000例胰腺癌确诊病例。胰腺癌是当今男性和女性最常见的第十种癌症，但它是导致癌症死亡的第四大原因。该病最常见的症状，黄疸、腹痛、体重减轻，以及其他表现因素，本质上都是非特异性的。因此，在肿瘤生长的早期阶段诊断胰腺癌充其量是困难的，需要相当大的怀疑和广泛的诊断工作，直到并包括探查手术。我们实验室已经开发并鉴定了PAM4单抗(鼠源性、嵌合型和人源化版本)，为其在胰腺癌临床检测、成像和治疗方面的潜力提供了证据。我们的最新进展是采用体外酶免疫分析法定量患者血液中的PAM4反应抗原，在检测胰腺癌及其与胰腺炎以及其他癌症和正常人的鉴别方面似乎非常有希望。早期发现和诊断胰腺癌，以及对疾病进行适当的分期，几乎肯定会提供生存优势。考虑到这一点，我们打算进一步开发和评估基于PAM4的免疫分析方法的能力，包括组织标本中的免疫组织化学检测和酶免疫分析，以检测和定量血清和胰液中的抗原，以便在治疗干预可能有更好的成功结果的时间点提供早期检测和诊断。本项目的具体目标是：1.评估PAM4-免疫分析的诊断准确性；2.评估PAM4-免疫分析对出现胰腺癌症状的患者进行准确诊断的临床应用；b-在无症状的胰腺癌高危人群中早期检测胰腺癌；c-评估肿瘤反应或早期检测复发；3.评估PAM4对抗原的反应性质。 公共卫生相关性：胰腺癌是一种死亡率特别高的隐匿性疾病。在很大程度上，这是由于肿瘤的位置，在那里它可以以沉默的方式生长。可能提示患者寻求医疗帮助的症状通常不明显，直到肿瘤生长到晚期。使这一挑战更加复杂的是，目前可用的治疗程序无法为绝大多数患者提供治愈方法。我们的目标是在治疗过程有更好的成功机会的时候，提供一种抗体方法来早期发现和诊断疾病。我们已经开发出对胰腺癌具有高度特异性的单抗PAM4，与良性胰腺疾病、其他类型的恶性肿瘤和正常人相比，PAM4对胰腺癌具有高度的特异性。因此，PAM4反应性抗原的检测为胰腺癌的诊断提供了很高的可能性。这项拟议研究的目的是进一步确定抗体提供准确诊断的能力的特异性，并在一组被认为有高风险发生胰腺癌的患者中检验免疫分析在胰腺癌出现症状之前“早期”发现该疾病的价值。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.