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

摘要 胰腺导管腺癌(PDAC)的中位5年生存率仅为8%，早期诊断为 PDAC是NCI最优先考虑的领域。公认的PDAC的危险因素之一是粘液性 胰腺囊肿，其中最常见的亚型是导管内乳头状黏液性肿瘤 (IPMN)。目前，IPMN患者要么由于“令人担忧的”影像特征而接受手术切除，要么 随后保守地进行了一系列影像研究，以确定进展为侵袭性PDAC的风险。不幸的是， 反映患者接受手术的影像标准不完善，导致IPMN治疗过度和治疗不足。 此外，目前还没有基于血液的生物标志物具有可靠的灵敏度和特异度。 治疗性分层。我们的小组已经确定KRAS和GNAS是最常见的两种致癌突变 IPMN中常见的驱动程序突变--约96%的病例中存在这样或那样的突变。我们现在已经设计了 第一个含有突变组合(Kras；GNas)的IPMN动物模型，最常见的是 同源人类疾病。在多西环素诱导下，Kras；GNas小鼠在6岁之前均匀地形成囊性病变 21周后，25%的小鼠进展为浸润性癌症，模拟多步进展 人类IPMN转PDAC。这项建议的目的是加强这一模式的翻译适用性 通过将其作为一个受控平台，在两个领域解决IPMN管理中未得到满足的关键需求： 成像与循环生物标记物相关。在目标1中，我们将使用动物模型来研究两部小说 成像平台.使用自主开发的算法从核磁共振扫描中提取定量特征 称为增强模式映射(EPM)和第二，超极化磁共振成像(HPMRI)，以便 确定与低级别IPMN向癌症转变相一致的影像相关性。在目标2中，我们将 结合使用无偏质谱和基于阵列的方法来鉴定循环蛋白质 和自身抗体，分别与小鼠IPMNS向PDAC的进展相关。此外，我们还将 通过利用一种超灵敏的和 滴状数字定量聚合酶链式反应(DdPCR)平台检测循环中突变的KRAS和GNAS DNA 外显体。所有三类基于血液的生物标志物(蛋白质、自身抗体和外源DNA)都将被评估。 在匹配的小鼠血浆样本中，这将使我们能够估计癌症检测的相加性能 使用稳健的统计范例。这两个目标都将受益于随时可以获得成像扫描和生物显微镜 来自IPMN患者的跨物种翻译验证研究，通过NCI资助的多中心U01 由PI领导的财团。我们相信，这项多学科的建议有可能产生长期影响。 通过实践改变癌症进展监测方法的变化来探讨PDAC死亡率 在IPMN中。

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.