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

 描述（由申请人提供） 尽管影像技术、手术和肿瘤治疗有所进步，但胰腺导管腺癌 (PDAC) 的临床结果在 40 年来并未改善。为了改善结果，必须开发新的成像功能，以实现 PDAC 的早期检测并识别可能进展为浸润性癌症的 PDAC 前驱病变。胰腺上皮内瘤变 (PanIN) 和导管内乳头状粘液性瘤变 (IPMN) 代表 PDAC 前驱病变的两类重要类型；这些病变之间的风险分层为有 PDAC 风险的患者提供了个性化医疗的独特机会。 我们鉴定出易位蛋白 (TSPO)，一种参与胆固醇代谢的 18 kDa 线粒体外膜蛋白，作为 PDAC 的潜在生物标志物。我们评估了人 PanIN、IPMN 和 PDAC 组织微阵列中的 TSPO 免疫反应性 (IHC)。与低级别 PanIN 和良性 IPMN 亚型相比，高级别人类 PanIN 病变和高级别 IPMN 亚型中 TSPO IHC 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 进展的基因工程小鼠 (GEM) 模型中评估 TSPO-PET 成像。在 Pft1a-Cre/ 中产生的 PanIN 中仅观察到 18[F] VUIIS-1008 和 TSPO IHC 水平的适度摄取； LSL-KrasG12D/ 小鼠，很少进展为 PDAC。相比之下，在 Pft1a-Cre/ 中产生的高级 PanIN 和 PDAC 中观察到 18[F]VUIIS-1008 的强劲摄取和相应增加的 TSPO IHC； LSL-KrasG12D/、Tgfbr2flox/。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导致 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 的两个 GEM，Ptf1a-Cre/ ;LSL-KrasG12D/ ;Smad4flox/flox，一个发展为晚期 IPMN 前体病变的模型，以及一个更具渗透性的模型 Ptf1a-Cre/ ;LSL-KrasG12D/ ;Smad4flox/flox;Ink4a/Arfflox/ ，开发可晋级 PDAC 的 IPMN。通过研究这些突变以及相关的病理学和影像学，我们将能够在当前的提案中，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 了解 PDAC 疾病进展中驱动 TSPO 表达的分子事件； [3] 研究人类胰腺组织，以确定突变状态、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 对 PDAC 高危患者的试验奠定基础。

 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.