Translational Applications in an Animal Model of Pancreatic Cystic Neoplasm and Cancer

胰腺囊性肿瘤和癌症动物模型中的转化应用

• 批准号: 9904574
• 负责人: ANIRBAN MAITRA
• 金额: $ 59.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-04 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904574
• 关键词: Abdomen; Address; Algorithms; Animal Model; Appendix Adenocarcinoma; Area; Autoantibodies; Benign; Biology; Cancer Detection; Cancer Etiology; Clinical; Credentialing; Cyst; Cystic Lesion; DNA; Data; Detection; Development; Diagnosis; Doxycycline; Early Diagnosis; Engineering; Excision; Funding; GTP-Binding Proteins; Genetic; Genetically Engineered Mouse; Genome; Genomics; Human; Image; Indigenous; Indolent; KRAS2 gene; Knowledge; Label; Laboratories; Lesion; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Modeling; Monitor; Mucinous Neoplasm; Mucins; Mus; Mutation; Neoplasms; Oncogenic; Operative Surgical Procedures; Pancreas; Pancreatic Cyst; Pancreatic Ductal Adenocarcinoma; Pancreatic cystic neoplasia; Papillary; Pathogenesis; Patients; Pattern; Performance; Plasma; Positioning Attribute; Protein Array; Proteins; Pyruvate; Recommendation; Reflex action; Risk; Risk Factors; Sampling; Scanning; Sensitivity and Specificity; Survival Rate; Time; Translational Research; United States; Validation; base; blood-based biomarker; cancer invasiveness; circulating biomarkers; cohort; digital; driver mutation; exosome; feature extraction; high risk; high risk population; human disease; imaging platform; imaging study; liquid biopsy; member; molecular imaging; mortality; mouse model; multidisciplinary; mutant; novel; overtreatment; pancreas imaging; patient population; prevent; progression marker; serial imaging; specific biomarkers; success; translational study; treatment stratification; tumor progression; validation studies

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has a median 5-year survival of only 8%, and early diagnosis of PDAC is an area of highest priority for the NCI. Amongst the best-recognized risk factors for PDAC are mucinous pancreatic cysts, of which the most common subtype is known as intraductal papillary mucinous neoplasm (IPMN). Currently, IPMN patients either undergo surgical resection due to “worrisome” imaging features, or are followed conservatively by serial imaging studies for risk of progression to invasive PDAC. Unfortunately, the imaging criteria reflexing patients to surgery are imperfect, leading to both over- and under-treatment of IPMNs. Further, there are no credentialed blood-based biomarkers with a sensitivity and specificity that warrants reliable therapeutic stratification. Our group has identified oncogenic mutations of KRAS and GNAS as the two most common driver mutations in IPMNs – one or other is present in ~96% of cases. We have now engineered the first animal model of IPMN that harbors the mutational combination (Kras;Gnas) found most commonly in the cognate human disease. Upon doxycycline induction, the Kras;Gnas mice uniformly develop cystic lesions by 6 weeks, with progression to invasive cancer in 25% of mice by 21 weeks, mimicking the multistep progression of human IPMN to PDAC. The objective of this proposal is to enhance the translational applicability of this model by using it as a controlled platform to address key unmet needs in the management of IPMNs in two areas: imaging correlates and circulating biomarkers. In Aim 1, we will use the animal model to investigate two novel imaging platforms – quantitative feature extraction from MRI scans using an indigenously developed algorithm known as “Enhancement Pattern Mapping” (EPM) and second, hyperpolarized MRI (HPMRI), in order to determine imaging correlates that coincide with the transition from low grade IPMN to cancer. In Aim 2, we will use a combination of unbiased mass spectrometry and array-based approaches to identify circulating proteins and autoantibodies, respectively that correlate with progression of murine IPMNs to PDAC. In addition, we will examine the potential of genomic liquid biopsies for cancer prediction, through utilizing an ultrasensitive and quantitative droplet digital PCR (ddPCR) platform for detection of mutant KRAS and GNAS DNA within circulating exosomes. All three classes of blood-based biomarkers (proteins, autoantibodies and exoDNA) will be assessed in matched murine plasma samples, which will allow us to estimate the additive performance for cancer detection using robust statistical paradigms. Both aims will benefit from ready access to imaging scans and biospecimens from IPMN patients for cross-species translational validation studies, through NCI-funded multicenter U01 consortia that are led by the PI. We believe this multidisciplinary proposal has the potential for long-term impact on PDAC mortality through practice changing alterations in the approach towards monitoring cancer progression in IPMNs.

抽象的 胰腺导管腺癌（PDAC）的中位5年生存率仅为8％，并且早期诊断 PDAC是NCI优先级最高的领域。在PDAC的最佳识别危险因素中，有粘液 胰腺囊肿，其中最常见的亚型被称为导管内乳头状粘液肿瘤 （IPMN）。目前，IPMN患者因“令人担忧”的成像功能而进行手术切除，或者是 紧随其后进行串行成像研究，以促进侵入性PDAC的风险。不幸的是， 反射患者进行手术的成像标准是不完善的，导致IPMN的过度和不足。 此外，没有具有敏感性和特异性的凭据基于血液的生物标志物值得可靠 治疗分层。我们的小组已经确定KRAS和GNA的致癌突变是两个 IPMN中的常见驱动突变 - 约96％的病例中存在一个或另一个。我们现在已经设计了 具有突变组合（KRAS; GNA）的IPMN的第一种动物模型 同源人类疾病。强力霉素诱导后，Kras; gNA小鼠均匀地形成了囊性病变。 周，随着25％的小鼠的侵入性癌症的发展，模仿了多步进 人类IPMN至PDAC。该提案的目的是增强该模型的翻译适用性 通过将其用作受控平台，以在两个领域的IPMN管理中解决关键未满足的需求： 成像与生物标志物相关和循环。在AIM 1中，我们将使用动物模型研究两种小说 成像平台 - 使用单独开发的算法从MRI扫描中提取定量特征 被称为“增强模式映射”（EPM）和第二个超极化MRI（HPMRI），以便为了 确定成像与从低级IPMN向癌症的过渡相吻合。在AIM 2中，我们将 使用无偏质谱和基于阵列的方法的组合来识别循环蛋白 和自身抗体，分别与鼠IPMN向PDAC的进展相关。此外，我们将 通过利用超敏感和 定量液滴数字PCR（DDPCR）平台用于检测突变的KRAS和GNA DNA循环中 外泌体。所有三类基于血液的生物标志物（蛋白质，自身抗体和埃及娜）将被评估 在匹配的鼠血浆样品中，这将使我们能够估算癌症检测的添加剂性能 使用强大的统计范例。两种目标都将受益于现成的成像扫描和生物测量 通过NCI资助的多中心U01，来自IPMN患者的跨物种转化验证研究 由PI领导的财团。我们认为，这项多学科提议有可能产生长期影响 通过改变监测癌症进展的方法的改变PDAC死亡率 在IPMN中。