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

TSPO-PET 对胰腺癌和高风险前体病变进行成像

• 批准号: 9273261
• 负责人: Jennifer M Watchmaker
• 金额: $ 4.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273261
• 关键词: Address; Age; Animal Model; Behavior; Benign; Breast; Cell physiology; Characteristics; Cholesterol Homeostasis; Clinical; Clinical Management; Colon; Controlled Study; Detection; Disease; Disease Progression; Early Diagnosis; Evaluation; Event; Excision; Family; Foundations; Future; Genetically Engineered Mouse; Genomics; Genotype; Glioma; Goals; Human; Image; Imaging Techniques; Laboratories; Lead; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane Proteins; Methods; Modeling; Molecular; Mucinous; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Operative Surgical Procedures; Oral; Outcome; Outer Mitochondrial Membrane; Pancreas; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Papillary; Pathology; Patients; Positron-Emission Tomography; Pre-Clinical Model; Premalignant; Proteins; Regulation; Resected; Risk; Risk stratification; Role; Sensitivity and Specificity; Severity of illness; Signal Pathway; Signaling Protein; Specimen; Staining method; Stains; Steroids; TGF Beta Signaling Pathway; Testing; Time; Tissue Microarray; Tissue Sample; Tissues; Tracer; Transforming Growth Factor beta; Work; advanced disease; base; cancer invasiveness; cell growth regulation; effective therapy; experimental study; high risk; human tissue; imaging capabilities; immunoreactivity; improved; improved outcome; insight; molecular imaging; mouse model; mutational status; novel; oncology; pancreas development; pancreas imaging; personalized medicine; potential biomarker; pre-clinical; preclinical study; profiles in patients; protein expression; public health relevance; receptor; tool; treatment strategy; tumor; tumor progression; uptake

 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.

 描述（由申请人提供） 尽管成像技术，手术和肿瘤治疗的改进，胰腺导管腺癌（PDAC）的临床结果在40年内仍未改善。为了改善结果，必须开发新的成像功能，以早日检测PDAC并鉴定可能发展为侵入性癌症的PDAC前体病变。胰腺内肿瘤（PANIN）和导管内乳头状粘液性肿瘤（IPMN）代表两种重要类PDAC前体病变；这些病变之间的风险分层代表了在患有PDAC风险的患者中个性化医学的独特机会。我们确定了易位蛋白（TSPO），这是一种18 kDa的线粒体膜蛋白参与胆固醇代谢，是PDAC的潜在生物标志物。我们在人类Panins，IPMN和PDAC的组织微阵列中评估了TSPO免疫反应性（IHC）。与低级Panin和良性IPMN亚型相比，高级人类Panin病变和IPMN的高级亚型中TSPO IHC升高。这些结果促使我们探索了Panins中TSPO水平升高的机理基础，并使用18 [F] VUIIS-1008 [F] VUIIS-1008（我们的实验室中开发的一种新型TSPO-PET配体）评估了Panin panin到PDAC进展的TSPO-PET成像。在Pft1a-cre/+中产生的PANIN中，仅观察到18 [F] VUIIS-1008的适度摄取； LSL-KRASG12D/+小鼠，很少会发展为PDAC。相比之下，在pft1a-cre/+中产生的高级PANIN和PDAC中观察到了18 [F] VUIIS-1008的强劲摄取，并相应地增加了TSPO IHC。 lsl-krasg12d/+，tgfbr2flox/+。综上所述，我们假设TGF-β信号通路途径通过直接或间接机制导致TSPO表达增加。为了进一步了解TSPO表达的临时调节，并探索其他TGF-β家族受体蛋白，我们建议检查PDAC的两颗宝石PTF1A-CRE/+; lsl-krasg12d/+; smad4flox/flox，这是一种发展了一种模型，该模型会发展出高级IPMN前体模型和更普遍的模型模型Ptf1a-cre/+; lsl-krasg12d/+; smad4flox/flox; ink4a/arfflox/+，开发了前进到PDAC的IPMN。通过研究这些突变以及相关的病理和成像，我们将能够在当前的建议中，我们寻求[1]确定TSPO-PET将高级别与低级PDAC前体区分开的能力； [2]使用GEM了解驱动PDAC疾病进展中TSPO表达的分子事件； [3]研究人类胰组织，以鉴定突变状态，TSPO表达和疾病严重程度之间的相关性，阐明了突变驱动TSPO信号的增加。我们预计这些研究将为评估高危患者的TSPO-PET的试验奠定基础，以开发PDAC。