Imaging Liver Cancer Proliferation

肝癌增殖成像

• 批准号: 9749959
• 负责人: Zhenghong Lee
• 金额: $ 36.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9749959
• 关键词: Animal Model; Attention; Biodistribution; Biopsy; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Clinical; Companions; Cytidine Deaminase; Cytidine Deaminase Inhibitor; Cytosine; DNA; Data; Deamination; Decitabine; Deoxycytidine; Deoxycytidine Kinase; Deoxyglucose; Development; Enzymes; Frequencies; Glucuronides; Goals; Hepatic; Hepatic Tissue; Image; Infection; Intestines; Lesion; Liver; Lymphoid; Malignant neoplasm of liver; Measures; Metabolism; Methods; Modeling; Nucleosides; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Phosphotransferases; Positron-Emission Tomography; Prediction of Response to Therapy; Primary carcinoma of the liver cells; Process; Proliferating; Radiolabeled; Resistance; Schedule; Signal Transduction; T-Lymphocyte; TP53 gene; Testing; Tetrahydrouridine; Thymidine; Thymidine Kinase; Thymine; Tracer; United States; Validation; Viral hepatitis; Woodchuck; analog; base; cancer therapy; cellular imaging; chemotherapy; clinically relevant; design; effective therapy; fluorodeoxyglucose; gemcitabine; glucose uptake; human imaging; imaging biomarker; imaging study; liver imaging; novel; novel strategies; novel therapeutics; oncology; patient subsets; pre-clinical; predicting response; public health relevance; radiotracer; rapid growth; recruit; response; small molecule; tripolyphosphate; tumor; uptake

 DESCRIPTION (provided by applicant): Hepatocellular Carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The main PET tracer currently used in oncology applications, 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), has been shown to be ineffective for imaging HCC since many HCCs do not show differential FDG uptake comparing to the surrounding hepatic tissues. Identification of aggressive liver lesions with rapid growth (proliferation) with PET imaging also proves to be difficult since several thymidine analogs (all substrates of thymidine kinase (TK)) developed for proliferation imaging did not work well in the liver due mainly to glucuronidation, which leads to a high liver background uptake. We propose to investigate a newly developed tracer, 1-(2'-deoxy- 2'-[18F]-fluoro-β-D-arabinofuranosyl)cytosine ([18F]-FAC, a substrate more specific for deoxycytidine kinase (dCK) than for TK), which displays a lower liver background uptake. A modifier, tetrahydrouridine (THU, an inhibitor of cytidine deaminase (CDA)), will be added to suppress enzymatic activity of hepatic CDA and maintain FAC activity in the liver. We plan to establish this [18F]-FAC and THU combination for PET imaging of proliferation in HCC based on encouraging preliminary pre-clinical results and clinical biodistribution studies. Our central hypothesis is that FAC uptak is correlated with dCK-dependent proliferation in HCC; and [18F]-FAC-PET (THU) can be used to identify aggressive HCC and to predict response to dCK-dependent treatment. We will test this hypothesis via the following Specific Aims. Aim 1: To confirm the mechanism of [18F]-FAC uptake in HCC with a clinically relevant woodchuck model of HCC; Aim 2: To validate [18F]-FAC-PET (THU) uptake in patients with HCC; Aim 3: To explore the utility of [18F]-FAC-PET (THU) as a companion imaging biomarker for predicting the response to novel dCK-dependent treatment such as the new therapeutic combination of THU-decitabine.

 描述（由应用提供）：肝细胞癌（HCC）是全球癌症死亡的第三主要原因。目前用于肿瘤学应用中的主要宠物示踪剂2- [18F] -Fluoro-2-脱氧-D-葡萄糖（FDG）被证明是对HCC成像的无效HCC，因为许多HCC并未显示出与周围的肝运动相比的差异FDG吸收。鉴定具有快速生长（增殖）和PET成像的攻击性肝病也很难，因为开发的几种胸苷类似物（所有用于增殖成像的胸苷激酶（TK）的底物（TK）的所有底物在肝脏中均无法很好地工作，这主要归因于腹泻，这导致了高肝脏背景。我们建议研究新开发的示踪剂1-（2'-脱氧2' - [18f] -fluoro-β-β-β-β-β-β-d- arabinofuranosyl）胞嘧啶（[18F] -FAC，一种比TK）比脱氧糖胞苷激酶（DCK）更具体的底物，而不是TK），这使得在低位级别的Liver Liver aupperstake中。将添加一种修饰剂四氢苷（THU，胞苷脱氨酶（CDA）），以抑制肝CDA的酶活性并维持肝脏中的FAC活性。我们计划基于鼓励初步的临床前结果和临床生物分布研究来建立这种[18F] -FAC和THU组合，用于HCC中增殖的PET成像。我们的中心假设是，FAC UPTAK与HCC中的DCK依赖性增殖相关。和[18F] -FAC-PET（THU）可用于识别侵略性HCC并预测对DCK依赖性治疗的反应。我们将通过以下特定目标检验该假设。目标1：确认HCC中[18F] -FAC吸收的机制，并具有临床相关的HCC木制模型；目标2：验证HCC患者的[18F] -FAC-PET（THU）摄取； AIM 3：探索[18F] -FAC-PET（THU）作为伴侣成像生物标志物的实用性，以预测对新型DCK依赖性治疗的反应，例如Thu-Decitabine的新治疗组合。