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.

抽象的 胰腺导管腺癌（PDAC）的生存率仅为6％，在 早期可切除阶段提高了生存率：<2 cm的节点阴性肿瘤> 30％；多达60％ 肿瘤<1 cm;而且，对于原位癌而言，本质上是现代的。目前，诊断只有20％ 胰腺癌由于局部浸润和远处转移而被切除。因此很早 PDAC的检测可能会对生存产生巨大影响。 与肿瘤相关的MUC1（TMUC1）在90％以上的PDAC上呈现 由于TMUC1也被释放到循环 PDAC，抗原可以用作综合策略中的血液和成像生物标志物 旨在尽早检测胰腺癌。我们已经开发了一种肿瘤特异性抗体TAB004， 特异性检测到TMUC1。该抗体（鼠和嵌合）的变体已用于 开发一种名为Agkura®个人评分（APS）的血清ELISA测试，该测试使用新颖的专利待定 过程以准确测量TMUC1浓度的小小增加，这与 PDAC的进展。在II期临床研究中，该测试准确地分化了 疾病的疾病进展。 TAB004抗体也已经完全 人源化（HTAB004）开发放射性成像。 在这个项目中，我们建议使用三种新型鼠标模型，这些模型在整个过程中具有人类MUC1 上皮：MUC1.TG，赞助的PDA.MUC1.TG，它发育于PDAC和非 - 需要他莫昔芬注射以启动PDAC进展的赞助PDA.MUC1.TG模型。这 pda.muc1.tg模型具有KRASG12D突变，并模仿胰腺的发作和进展 人类的癌症。老鼠将在UNCC维持，每两人都会受到血液的抽血 几周。血液样本将以盲目的方式提供给Oncotab（与鼠标相关 模型将被扣留）测试APS测试在癌症现场阶段检测PDAC的能力。 标记为阳性的小鼠将被运送到Invicro，以用impium-111标记的HTAB004进行成像。 为了确保成像研究也被视而不见，没有PDAC的小鼠的两倍（MUC1.TG和非 - 赞助PDA.MUC.TG模型也将发货，而无需披露模型关联。 这三种鼠标模型在C57BL/6背景上，彼此无法区分。 成功演示了综合血清和成像生物标志物方法，以检测在A处的PDAC 拟议的盲目研究的原位癌将是一个重大突破。早期建立 在拟议的新型小鼠模型中检测模仿人PDAC进展将使阶段置于 通过APS测试进行临床试验，以筛查患有胰腺癌的高风险的人。