Imaging Liver Cancer Proliferation

肝癌增殖成像

• 批准号: 9980303
• 负责人: Zhenghong Lee
• 金额: $ 14.16万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980303
• 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; Malignant neoplasm of liver; Measures; Metabolism; Methods; Modeling; Nucleosides; Oncology; Operative Surgical Procedures; 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; lymphoid organ; novel; novel strategies; novel therapeutics; 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（由申请人提供）：肝细胞癌（HCC）是全世界癌症死亡的第三大原因。目前肿瘤学应用中使用的主要 PET 示踪剂 2-[18F]-氟-2-脱氧-D-葡萄糖 (FDG) 已被证明对 HCC 成像无效，因为许多 HCC 与周围肝组织相比没有显示出差异的 FDG 摄取。事实证明，用 PET 成像识别快速生长（增殖）的侵袭性肝脏病变也很困难，因为用于增殖成像的几种胸苷类似物（胸苷激酶 (TK) 的所有底物）在肝脏中效果不佳，主要是由于葡萄糖醛酸化，从而导致肝脏背景摄取较高。我们建议研究一种新开发的示踪剂 1-(2'-脱氧-2'-[18F]-氟-β-D-阿拉伯呋喃糖基)胞嘧啶（[18F]-FAC，一种对脱氧胞苷激酶 (dCK) 比对 TK 更具特异性的底物），它显示出较低的肝脏背景摄取。添加修饰剂四氢尿苷（THU，胞苷脱氨酶（CDA）抑制剂）以抑制肝脏 CDA 的酶活性并维持肝脏中的 FAC 活性。基于令人鼓舞的初步临床前结果和临床生物分布研究，我们计划建立这种 [18F]-FAC 和 THU 组合，用于 HCC 增殖的 PET 成像。我们的中心假设是 FAC uptak 与 HCC 中 dCK 依赖性增殖相关。 [18F]-FAC-PET (THU) 可用于识别侵袭性 HCC 并预测对 dCK 依赖性治疗的反应。我们将通过以下具体目标来检验这一假设。目标1：通过临床相关的HCC土拨鼠模型证实HCC中[18F]-FAC摄取的机制；目标 2：验证 HCC 患者对 [18F]-FAC-PET (THU) 的摄取；目标 3：探索 [18F]-FAC-PET (THU) 作为伴随成像生物标志物的实用性，用于预测对新型 dCK 依赖性治疗（例如 THU-地西他滨的新治疗组合）的反应。