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%， PDAC是NCI最优先考虑的领域。PDAC最常见的危险因素是粘液性 胰腺囊肿，其中最常见的亚型是导管内乳头状粘液性肿瘤 （IPMN）。目前，IPMN患者要么由于“令人担忧的”成像特征而接受手术切除，要么 随后进行保守的系列影像学研究，以评估进展为侵袭性PDAC的风险。可惜 反映患者手术的成像标准是不完善的，导致IPMN的过度治疗和治疗不足。 此外，没有可信的血液生物标志物具有可靠的灵敏度和特异性， 治疗分层我们的小组已经确定KRAS和GNAS的致癌突变是两个最重要的基因突变。 IPMN中常见的驱动突变-约96%的病例中存在一种或另一种。我们现在设计了 IPMN的第一个动物模型，该模型携带在哺乳动物中最常见的突变组合（Kras;Gnas）。 人类同源疾病在多西环素诱导后，Kras;Gnas小鼠在6小时内均匀地发展出囊性病变。 21周时，25%的小鼠进展为浸润性癌症，模拟了肿瘤的多步进展。 人IPMN对PDAC。本提案的目的是提高该模型的翻译适用性 将其作为一个受控平台，以解决IPMN管理中两个领域未满足的关键需求： 成像相关性和循环生物标志物。在目标1中，我们将使用动物模型来研究两种新的 成像平台--使用自主开发的算法从MRI扫描中提取定量特征 称为“增强模式映射”（Enhancement Pattern Mapping，HPM）和第二种超极化MRI（hyperpolarized MRI，HPMRI），以便 确定与从低级别IPMN到癌症的转变相一致的成像相关性。在目标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质 和自身抗体，分别与鼠IPMN向PDAC的进展相关。此外，我们将 研究基因组液体活检预测癌症的潜力，通过利用超灵敏， 定量液滴数字PCR（ddPCR）平台，用于检测循环中的突变KRAS和GNAS DNA 外来体将评估所有三类血液生物标志物（蛋白质、自身抗体和exoDNA） 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附加性能 使用强大的统计范例。这两个目标都将受益于成像扫描和生物标本的快速获取 来自IPMN患者的跨物种翻译验证研究，通过NCI资助的多中心U 01 由私家侦探领导的财团我们认为，这一多学科的建议具有长期影响的潜力 通过实践改变监测癌症进展的方法， 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.