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

使用血清和成像生物标志物早期检测胰腺癌的综合策略。

• 批准号: 10325659
• 负责人: Pinku Mukherjee
• 金额: $ 40万
• 依托单位: ONCOTAB, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325659
• 关键词: Address; Adenocarcinoma; Animals; Antibodies; Antigens; Apical; Benign; Biochemical; Biological; Biological Markers; Blinded; Blood; Blood Circulation; Blood Tests; Blood specimen; Breast Cancer Detection; Cancer Etiology; Carcinoma in Situ; Cells; Cessation of life; Clinic; Clinical Research; Clinical Trials; Detection; Development; Diagnosis; Diagnostic Services; Disease; Disease Progression; Distant Metastasis; Duct (organ) structure; Early Diagnosis; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Excision; Glycoproteins; Goals; Growth; High Prevalence; Histologic; Histology; Human; Image; Immunohistochemistry; India; Indium-111; Infiltration; Injections; KRASG12D; Label; Legal patent; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Modeling; Monitor; Mucin 1 protein; Mucins; Mus; Mutation; N-terminal; Neoplasm Metastasis; Normal Cell; Operative Surgical Procedures; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Patients; Performance; Phase; Process; Proteins; Radioisotopes; Radionuclide Imaging; Research; Resectable; Sensitivity and Specificity; Serum; Ships; Signal Transduction; Source; Stable Disease; Surface; Survival Rate; Symptoms; Tamoxifen; Test Result; Testing; Time; Tumor Antigens; Tumor Markers; Variant; Work; base; cellular imaging; cohort; design; early detection biomarkers; first-in-human; fluorophore; high risk; imaging biomarker; imaging study; improved; in vivo imaging; mortality; mouse model; novel; pre-clinical; screening; targeted treatment; theranostics; tumor

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.

摘要 胰腺导管腺癌（PDAC）的5年生存率仅为6%， 早期切除可提高生存率：淋巴结阴性肿瘤< 2 cm>> 30%; 肿瘤< 1 cm;并且，原位癌基本上是治愈性的。目前，诊断时只有20%的 胰腺癌由于局部浸润和远处转移是可切除的。因此，早 PDAC的检测可以对生存产生显著影响。 肿瘤相关MUC 1（tMUC 1）存在于90%以上的PDAC上， 免疫组化由于tMUC 1也被释放到循环中，因此考虑到 PDAC抗原可在综合策略中用作基于血液的生物标志物和成像生物标志物 旨在早期发现胰腺癌。我们已经开发了肿瘤特异性抗体TAB 004， 其特异性地检测tMUC 1。该抗体的变体（鼠和嵌合）已用于 开发一种名为Agkura®个人评分（APS）的血清ELISA测试，该测试使用一种正在申请专利的新方法， 过程，以准确地测量tMUC 1浓度的小幅增加，这与 PDAC的进展在一项II期临床研究中，该测试准确区分了患有以下疾病的患者： 病情稳定的患者病情进展。TAB 004抗体也已完全 人源化（hTAB 004）以进行放射性核素成像。 在这个项目中，我们建议使用三种新的小鼠模型，在整个小鼠模型中具有人MUC 1。 上皮细胞：MUC1.Tg，自发PDA.MUC1.Tg，其自发发展PDAC和非PDAC。 需要他莫昔芬注射以启动PDAC进展的自发PDA.MUC1.Tg模型。的 PDA.MUC1.Tg模型具有KRASG 12 D突变并模拟胰腺癌的发作和进展。 人类的癌症这些小鼠将在联合国赔偿委员会饲养，每两周抽血一次。 周将以设盲方式向OncoTAb提供血液样本（与小鼠相关）。 模型将被扣留），以测试APS测试在原位癌阶段检测PDAC的能力。 将标记为阳性的小鼠运送至Invicro，用铟-111标记的hTAB 004进行成像。 为了确保成像研究也是盲的，将没有PDAC（MUC1.Tg和非PDAC）的小鼠的数量增加两倍。 自发的PDA.MUC.Tg型号）也将在不披露型号关联的情况下进行装运。 这三种小鼠模型在C57 BL/6背景下，彼此无法区分。 成功证明了综合血清和成像生物标志物方法可检测PDAC， 原位癌阶段的盲法研究将是一个重大突破。建立早期 在所提出的模拟人类PDAC进展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。