TSPO-PET to Image Pancreatic Cancer and High-Risk Precursor Lesions

 描述（由申请人提供） 尽管影像学技术、手术和肿瘤学治疗有所改进，但胰腺导管腺癌（PDAC）的临床结局在40年内没有改善。为了改善预后，必须开发新的成像能力，使PDAC的早期检测和识别可能进展为浸润性癌症的PDAC前体病变。胰腺上皮内瘤变（PanIN）和导管内乳头状粘液瘤变（IPMN）代表了两类重要的PDAC前体病变;这些病变之间的风险分层代表了有发生PDAC风险的患者个性化用药的独特机会。 我们确定了转运蛋白（TSPO），一个18 kDa的线粒体外膜蛋白参与胆固醇代谢，作为PDAC的一个潜在的生物标志物。我们在人PanIN、IPMN和PDAC的组织微阵列中评估了TSPO免疫反应性（IHC）。与低级别PanIN和良性IPMN亚型相比，TSPO IHC在高级别人类PanIN病变和高级别IPMN亚型中升高。这些结果促使我们探索PanIN中TSPO水平升高的机制基础，并使用我们实验室开发的新型TSPO-PET配体18[F] VUIIS-1008在PanIN至PDAC进展的遗传工程小鼠（GEM）模型中评价TSPO-PET成像。在Pft 1a-Cre/+; LSL-KrasG 12 D/+小鼠中产生的PanIN中仅观察到18[F] VUIIS-1008和TSPO IHC水平的适度摄取，其很少进展为PDAC。相比之下，在Pft 1a-Cre/+、LSL-KrasG 12 D/+、Tgfbr 2flox/+中产生的高级别PanIN和PDAC中观察到18[F]VUIIS-1008的稳健摄取和相应增加的TSPO IHC。综上所述，我们假设TGF-β信号通路扰动通过直接或间接机制引起TSPO表达增加。为了进一步了解TSPO表达的时间调节，并探索其他TGF-β家族受体蛋白，我们建议检查PDAC的两种GEM，Ptf 1a-Cre/+; LSL-KrasG 12 D/+; Smad 4flox/flox，一种发展晚期IPMN前体病变的模型，以及一种更渗透的模型Ptf 1a-Cre/+; LSL-KrasG 12 D/+; Smad 4flox/flox; Ink 4a/Arfflox/+，其发展进展为PDAC的IPMN。通过研究这些突变和相关的病理学和成像，我们将能够在目前的提议中，我们寻求[1]确定TSPO-PET区分高级别和低级别PDAC前体的能力; [2]使用GEM来理解在PDAC疾病进展中驱动TSPO表达的分子事件;[3]确定TSPO-PET在PDAC疾病进展中的作用。和[3]研究人胰腺组织以鉴定突变状态、TSPO表达和疾病严重程度之间的相关性，阐明哪些突变驱动TSPO信号增加。我们预计，这些研究将为评估TSPO-PET在发展PDAC的高风险患者中的试验奠定基础。

 DESCRIPTION (provided by applicant) Despite improvements in imaging techniques, surgery, and oncologic treatments, clinical outcomes for pancreatic ductal adenocarcinoma (PDAC) has not improved in 40 years. To improve outcomes, it is imperative to develop new imaging capabilities that enable early detection of PDAC and to identify PDAC precursor lesions that are likely to progress to invasive cancer. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN) represent two important classes of PDAC precursor lesions; risk stratification among these lesions represents a unique opportunity for personalized medicine in patients at risk for developing PDAC. We identified translocator protein (TSPO), an 18 kDa outer mitochondrial membrane protein involved in cholesterol metabolism, as a potential biomarker of PDAC. We evaluated TSPO immunoreactivity (IHC) in tissue microarrays of human PanINs, IPMNs, and PDAC. TSPO IHC was elevated in high-grade human PanIN lesions and high-grade subtypes of IPMN compared to low-grade PanIN and benign IPMN subtypes. These results prompted our exploration of the mechanistic basis of elevated TSPO levels in PanINs and evaluation of TSPO-PET imaging in genetically engineered mouse (GEM) models of PanIN to PDAC progression using 18[F] VUIIS-1008, a novel TSPO-PET ligand developed in our laboratory. Only modest uptake of 18[F] VUIIS-1008 and TSPO IHC levels were observed in PanINs arising in Pft1a-Cre/+; LSL- KrasG12D/+ mice, which rarely progress to PDAC. In contrast, robust uptake of 18[F]VUIIS-1008 and correspondingly increased TSPO IHC was observed in high-grade PanINs and PDACs arising in Pft1a-Cre/+; LSL-KrasG12D/+, Tgfbr2flox/+. Taken together, we hypothesize that TGF-β signaling pathway perturbations cause increased TSPO expression, via direct or indirect mechanisms. To further understand the temporal regulation of TSPO expression, and explore other TGF-β family receptor proteins, we propose examining two GEM of PDAC, Ptf1a-Cre/+;LSL-KrasG12D/+;Smad4flox/flox, a model that develops advanced IPMN precursor lesions, and a more penetrant model Ptf1a-Cre/+;LSL-KrasG12D/+;Smad4flox/flox;Ink4a/Arfflox/+, that develops IPMNs that advance to PDAC. By studying these mutations and correlative pathology and imaging, we will be able to In the current proposal, we seek to [1] Determine the ability of TSPO-PET to distinguish high-grade from low-grade PDAC precursors; [2] Use GEM to understand the molecular events that drive TSPO expression in PDAC disease progression; and [3] Study human pancreatic tissue to identify correlations between mutational status, TSPO expression, and disease severity, elucidate which mutations drive increased TSPO signal. We anticipate that these studies will lay the foundation for a trial evaluating TSPO-PET in patients at high-risk for developing PDAC.