An integrated strategy using a serum and imaging biomarker for the early detection of pancreatic cancer.

摘要 胰腺导管腺癌(PDAC)的5年生存率仅为6%，诊断为胰腺癌。 早期可切除可提高存活率：结节阴性肿瘤30%；2厘米；高达60% 肿瘤&lt；1厘米；和，基本治愈原位癌。目前，确诊时只有20%的人 胰腺癌由于局部浸润性和远处转移是可以切除的。因此很早 PDAC的检测对患者的生存有很大影响。 肿瘤相关MUC1(TMUC1)存在于90%以上的PDAC上，通过 免疫组织化学。由于tMUC1也被释放到循环中，鉴于 在综合策略中，该抗原可用作基于血液的生物标记物和成像生物标记物 旨在及早发现胰腺癌。我们已经开发出一种肿瘤特异性抗体TAB004， 它专门检测tMUC1。这种抗体的变种(鼠型和嵌合型)已被用于 开发一种名为Agkura®Personal Score(APS)的血清ELISA测试，该测试使用一种正在申请专利的新技术 精确测量tMUC1浓度小幅增加的过程，这与 PDAC的进展。在一项II期临床研究中，这项测试准确地区分了 疾病从病情稳定的人发展而来。TAB004抗体也已完全 人源化(HTAB004)，以开发放射性核素成像。 在这个项目中，我们建议使用三种新的小鼠模型，它们完全具有人类MUC1 上皮细胞：MUC1.Tg，自发的PDA，MUC1.Tg，自发发展的PDAC和非 需要注射他莫昔芬才能启动PDAC进展的自发性PDA-MUC1.Tg模型。这个 PDA.MUC1.Tg模型存在KrasG12D突变并模拟胰腺癌的发生发展 人类的癌症。这些小鼠将被保存在赔偿委员会，并每两次抽血一次 几周。血样将以盲法提供给OncoTAb(与小鼠关联 模型将被扣留)，以测试APS测试在原位癌阶段检测PDAC的能力。 标记为阳性的小鼠将被运往Invicro进行用铟-111标记的hTAB004进行成像。 为了确保成像研究也是盲目的，没有PDAC的小鼠数量是对照组的两倍(MUC1.Tg和非 自发的PDA.MUC.Tg型号)也将在不披露型号关联的情况下发货。 这三个小鼠模型都是在C57BL/6的背景上，彼此无法区分。 血清和影像生物标记物综合方法检测PDAC的成功示范 原位癌在提出的盲法研究中将是一个重大突破。及早建立 在所提出的模仿人类PDAC进程的新型小鼠模型中的检测将为 进行一项临床试验，使用APS测试筛查胰腺癌高危人群。

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 6% and diagnosis at an earlier resectable stage improves survival rates: > 30% for node negative tumors < 2 cm; up to 60% for tumors < 1 cm; and, essentially curative for carcinoma in situ. Currently, at diagnosis only 20% of pancreatic cancers are resectable due to locoregional infiltration and distant metastases. Hence early detection of PDAC can have a dramatic impact on survival. Tumor associated MUC1 (tMUC1) is present on over 90% of PDAC examined by immunohistochemistry. Since tMUC1 is also released into circulation, given the high prevalence in PDAC, the antigen can be used as both a blood based and imaging biomarker in an integrated strategy designed to detect pancreatic cancer early. We have developed a tumor specific antibody, TAB004, which specifically detects tMUC1. Variants of this antibody (murine and chimeric) have been used to develop a serum ELISA test called the Agkura® Personal Score (APS) that uses a novel patent pending process to accurately measure small increases in tMUC1 concentration which are associated with the progression of PDAC. In a Phase II clinical study, this test accurately differentiated patients with disease progression from those with stable disease. The TAB004 antibody has also been fully humanized (hTAB004) to develop radionuclide imaging. In this project we propose to use three novel mouse models that have human MUC1 in the entire epithelia: MUC1.Tg, spontaneous PDA.MUC1.Tg that spontaneously develops PDAC and a non- spontaneous PDA.MUC1.Tg model that requires tamoxifen injection to initiate PDAC progression. The PDA.MUC1.Tg models have the KRASG12D mutation and mimic the onset and progression of pancreatic cancer in humans. The mice will be maintained at UNCC and be subjected to blood draws every two weeks. Blood samples will be provided to OncoTAb in a blinded fashion (association with mouse model will be withheld) to test the ability of the APS test to detect PDAC at a carcinoma in situ stage. Mice flagged positive will be shipped to Invicro for imaging with hTAB004 labeled with Indium-111. To ensure the imaging study is also blinded, twice as many mice without PDAC (MUC1.Tg and non- spontaneous PDA.MUC.Tg models) will also be shipped without model association being disclosed. The three mouse models are on the C57BL/6 background and are indistinguishable from each other. Successful demonstration of the integrated serum and imaging biomarker approach to detect PDAC at a carcinoma in situ stage in the proposed blinded study will be a major breakthrough. Establishing early detection in the proposed novel mouse model that mimics human PDAC progression will set the stage to conduct a clinical trial to screen people at high risk for pancreatic cancer using the APS test.