Functional Genomics and Molecular Imaging of Liver Disease and Cancer

肝病和癌症的功能基因组学和分子成像

• 批准号: 8867166
• 负责人: Sandi Alexander Kwee
• 金额: $ 41.17万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867166
• 关键词: Accounting; Address; BAY 54-9085; Biological; Biological Markers; Cancer Detection; Cancer Etiology; Cell membrane; Characteristics; Choline; Choline Kinase; Clinic; Clinical; Clinical Trials; Clinical/Radiologic; Correlation Studies; DNA Microarray Chip; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Early Diagnosis; Evaluation; Excision; Freezing; Gene Expression Profile; Gene Expression Profiling; Genes; Genome; Genomics; Goals; Gold; Health; Hepatic; Hepatocyte; Histopathology; Human; Image; Imaging Techniques; Incidence; Kinetics; Knowledge; Lead; Lecithin; Lesion; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Liver neoplasms; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Membrane; Metabolic; Metabolism; Mitogen-Activated Protein Kinases; Mitosis; Modality; Modeling; Molecular; Molecular Probes; Molecular Profiling; Molecular Target; Monitor; Morbidity - disease rate; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Patients; Performance; Pharmacotherapy; Phospholipid Metabolism; Phospholipids; Phosphorylation; Phosphorylcholine; Pilot Projects; Play; Positron-Emission Tomography; Primary carcinoma of the liver cells; Proto-Oncogene Proteins c-akt; Receiver Operating Characteristics; Reference Standards; Relative (related person); Research; Residual state; Risk; Role; Second Messenger Systems; Severity of illness; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Source; Specimen; Staging; Stratification; Survivors; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Sample; Tissues; Tracer; Tumor Tissue; United States; United States National Institutes of Health; Up-Regulation; Work; X-Ray Computed Tomography; base; burden of illness; chronic liver disease; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; functional genomics; glucose metabolism; human FRAP1 protein; imaging modality; in vivo; innovation; liver function; liver imaging; molecular imaging; mortality; novel; novel diagnostics; novel strategies; novel therapeutics; outcome forecast; predictive marker; prognostic value; programs; response; screening; second messenger; stem; surveillance strategy; targeted imaging; targeted treatment; therapeutic target; trait; treatment planning; treatment response; tumor; tumorigenic

DESCRIPTION (provided by applicant): HCC is the fourth most common cancer in the world and third leading cause of cancer mortality worldwide. In the United States, HCC incidence continues to increase with an estimated 24,120 new cases diagnosed in 2010. The prognosis for this disease is poor even at early stage with a 5 year survival of 26% compared to only 2% when it is metastatic. Surgery is considered the best treatment option for hepatocellular carcinoma, but only if the disease is caught early and has not metastasized. Unfortunately, current imaging strategies for hepatocellular carcinoma (HCC) have a tendency to underestimate disease burden and extent, exposing patients who are not true surgical candidates to unnecessary morbidity, risks, and expense. Many patients with HCC also have underlying liver fibrosis or cirrhosis, and the health of the remnant liver is important in determining whether surgery is tolerable. Imaging also has not played enough of a role in assessing or predicting residual liver function in patients who are deemed surgical candidates. In addition, with the advent of molecular therapies for HCC such as sorafenib, imaging has not yet found a place in predicting or monitoring HCC response to therapeutic agents. The NIH Action Plan for Liver Disease Research calls for the development of new imaging techniques that can be applied clinically to HCC and chronic liver disease, and has identified Positron Emission Tomography (PET) as a promising technology that may address some of these issues. Unregulated phosphocholine synthesis is a feature found in many cancers that has also been observed in HCC. It is the target for a number of novel diagnostic and therapeutic strategies under development. How- ever, it is not certain at this time whether the changes in choline phospholipid metabolism are due to an in- creased demand for membrane phospholipids or an increase in mitogenic signaling, given that phosphocholine is both a membrane phospholipid and important second messenger in Ras mediated mitogenic pathways such as the MAPK and PI3K-AKT-mTOR pathways. The detection of both primary and metastatic HCC on the basis of enhanced tumor phosphocholine synthesis is feasible using positron emission tomography (PET) with the investigational tracer substrate of choline kinase, [18F]-fluoromethylcholine (FCH). However, the overall accuracy of FCH PET for HCC has not been formally tested, and the molecular mechanisms leading to choline kinase up regulation are still not yet determined for HCC. The aims of the proposed project are to: 1) Conduct a radiologic-pathologic correlation study collecting fresh frozen liver tissue specimens for correlation with FCH PET/CT to evaluate its diagnostic performance as a liver imaging modality for HCC, 2) Longitudinally assess liver function and disease outcome in HCC survivors to evaluate the clinical value of FCH PET/CT as a measure of hepatocyte function and prognostic value of transcriptional signatures obtained at the time of surgical resection of HCC. This novel integration between functional genomics and the evaluation of FCH PET/CT will determine the relative importance of phosphocholine metabolism as a diagnostic and therapeutic target in HCC and chronic liver disease, and advance our knowledge of the molecular mechanisms associated with the initiation and progression of HCC. This proposal is submitted in response to NIH PA-08-243.

描述（由申请人提供）：HCC是世界上第四大最常见的癌症，也是全球癌症死亡率的第三大主要原因。在美国，HCC发病率持续增加，估计在2010年被诊断出的24,120例新病例。该疾病的预后即使在早期阶段也很差，而5年生存率为26％，而转移性则仅为2％。手术被认为是肝细胞癌的最佳治疗选择，但前提是该疾病早期被捕并且尚未转移。不幸的是，当前的肝细胞癌（HCC）的成像策略倾向于低估疾病负担和程度，暴露于不是真正的手术候选者的患者，以可能出现不必要的发病率，风险和费用。许多HCC患者还具有潜在的肝纤维化或肝硬化，残留肝脏的健康对于确定手术是否可以忍受很重要。成像在评估或预测被认为是手术候选患者的残留肝功能方面还没有发挥足够的作用。此外，随着索拉非尼等HCC分子疗法的出现，成像尚未在预测或监测对治疗剂的HCC反应方面的位置。 NIH肝病研究计划要求开发新的成像技术，这些技术可以在临床上应用于HCC和慢性肝病，并确定正电子发射断层扫描（PET）是一种有希望的技术，可以解决其中一些问题。不调节的磷胆碱合成是在许多癌症中发现的特征，在HCC中也观察到。它是许多正在开发的新型诊断和治疗策略的目标。但是，目前尚不确定胆碱代谢的变化是由于对膜磷脂的需求不足，鉴于磷酸胆碱是膜磷脂的膜磷脂和RAS介导的二裂途径的第二墨西哥膜，例如绘制有丝分裂的途径，例如映射途径，例如绘制的磷酸磷脂，例如，绘制的磷酸磷脂途径，例如，映射途径和pii3k-ras。使用正电子发射断层扫描（PET）与胆碱激酶的研究示踪剂底物，[18F] - 氟甲基胆碱（FCH）一起，使用正电子发射断层扫描（PET）检测原代和转移性HCC是可行的。但是，尚未对HCC的FCH PET的总体准确性进行正式测试，并且导致胆碱激酶UP调节的分子机制尚未确定HCC。 The aims of the proposed project are to: 1) Conduct a radiologic-pathologic correlation study collecting fresh frozen liver tissue specimens for correlation with FCH PET/CT to evaluate its diagnostic performance as a liver imaging modality for HCC, 2) Longitudinally assess liver function and disease outcome in HCC survivors to evaluate the clinical value of FCH PET/CT as a measure of hepatocyte function and在HCC手术切除时获得的转录特征的预后价值。功能基因组学与FCH PET/CT的评估之间的这种新颖的整合将决定磷胆碱代谢作为HCC和慢性肝病中的诊断和治疗靶标的相对重要性，并促进我们对与HCC起始和进展相关的分子机制的了解。该提案是根据NIH PA-08-243提交的。