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: 9051613
• 负责人: Jennifer M Watchmaker
• 金额: $ 2.79万
• 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/9051613
• 关键词: Address; Age; Animal Model; Behavior; Benign; Breast; Cell physiology; Characteristics; Cholesterol Homeostasis; Clinical; Clinical Management; Clinical Treatment; Colon; Controlled Study; Cystic Lesion; Detection; Development; 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; Methods; Mitochondrial Membrane Protein; 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; Role; Sensitivity and Specificity; Severity of illness; Signal Pathway; Signaling Protein; Specimen; Staging; Staining method; Stains; Steroids; Stratification; Surgical Oncology; TGF Beta Signaling Pathway; Testing; Time; Tissue Microarray; Tissue Sample; Tissues; Tracer; Transforming Growth Factor beta; Work; advanced disease; base; cell growth regulation; effective therapy; high risk; human tissue; immunoreactivity; improved; improved outcome; insight; meetings; molecular imaging; mouse model; mutational status; novel; oncology; personalized medicine; potential biomarker; pre-clinical; preclinical study; profiles in patients; protein expression; public health relevance; receptor; research study; 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) 尽管在成像技术、手术和肿瘤治疗方面有所改进，但40年来，胰腺导管腺癌(PDAC)的临床结果并没有改善。为了改善预后，必须开发新的成像能力，使PDAC能够及早发现，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(IPMN)是两类重要的PDAC前体病变；这些病变之间的风险分层为有PDAC风险的患者提供了独特的个体化药物治疗机会。我们发现转位蛋白(TransLocator Protein，TSPO)是参与胆固醇代谢的18 kDa线粒体外膜蛋白，是PDAC潜在的生物标志物。我们评估了人Panins、IPMns和PDAC组织芯片中的TSPO免疫反应性(IHC)。与低度恶性PAIN和良性IPMN亚型相比，高级别PAIN皮损和高级别IPMN患者TSPO IHC升高。这些结果促使我们探索Panins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向PDAC进展的基因工程小鼠(GEM)模型中评估TSPO-PET成像。在Pft1a-Cre/+；LSL-KrasG12D/+小鼠中仅观察到适度摄取18[F]VUIIS-1008和TSPO IHC水平，很少进展为PDAC。相反，在Pft1a-Cre/+、LSL-KrasG12D/+、Tgfbr2Flox/+出现的高级别PANI和PDAC中，观察到强劲的18[F]VUIIS-1008摄取和相应增加的TSPO IHC。综上所述，我们假设转化生长因子-β信号通路的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表达的时间调控，并探索其他转化生长因子受体家族蛋白，我们建议研究PDAC的两个GEM，Ptf1a-Cre/+；LSL-KrasG12D/+；Smad4Flox/Flox，一个发展晚期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/+，，它发展成PDAC的IPMN。通过研究这些突变以及相关的病理学和成像，我们将能够在目前的提议中，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来了解在PDAC疾病进展中驱动TSPO表达的分子事件；以及[3)研究人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，阐明哪些突变导致了TSPO信号的增加。我们预计，这些研究将为评估发生PDAC的高危患者的TSPO-PET试验奠定基础。