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: 8658047
• 负责人: Sandi Alexander Kwee
• 金额: $ 8.58万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658047
• 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; prognostic; programs; response; screening; second messenger; stem; surveillance strategy; 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 是世界上第四大常见癌症，也是世界上第三大癌症死亡原因。在美国，HCC 发病率持续增加，2010 年估计有 24,120 例新诊断病例。即使在早期，这种疾病的预后也很差，5 年生存率为 26%，而转移时仅为 2%。手术被认为是肝细胞癌的最佳治疗选择，但前提是疾病必须及早发现并且尚未转移。不幸的是，当前肝细胞癌 (HCC) 的影像学策略倾向于低估疾病负担和程度，使不适合手术的患者面临不必要的发病率、风险和费用。许多 HCC 患者还患有潜在的肝纤维化或肝硬化，残余肝脏的健康状况对于决定是否可以耐受手术非常重要。影像学在评估或预测被认为适合手术的患者的残余肝功能方面也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，影像学尚未在预测或监测 HCC 对治疗药物的反应中找到一席之地。美国国立卫生研究院肝病研究行动计划呼吁开发可临床应用于 HCC 和慢性肝病的新成像技术，并确定正电子发射断层扫描 (PET) 是一项有前景的技术，可以解决其中一些问题。磷酸胆碱合成不受调节是许多癌症中发现的一个特征，在肝癌中也观察到了这一特征。它是许多正在开发的新型诊断和治疗策略的目标。然而，鉴于磷酸胆碱既是膜磷脂，又是Ras介导的有丝分裂途径（例如MAPK和PI3K-AKT-mTOR途径）中重要的第二信使，目前尚不确定胆碱磷脂代谢的变化是由于对膜磷脂的需求增加还是促有丝分裂信号传导的增加。使用正电子发射断层扫描 (PET) 和胆碱激酶研究示踪底物 [18F]-氟甲基胆碱 (FCH)，基于增强的肿瘤磷酸胆碱合成来检测原发性和转移性 HCC 是可行的。然而，FCH PET 对 HCC 的总体准确性尚未经过正式测试，并且导致 HCC 胆碱激酶上调的分子机制仍未确定。该项目的目标是：1) 开展放射病理相关性研究，收集新鲜冷冻肝组织标本，与 FCH PET/CT 进行相关性研究，以评估其作为 HCC 肝脏成像方式的诊断性能，2) 纵向评估 HCC 幸存者的肝功能和疾病结果，以评估 FCH PET/CT 作为肝细胞功能指标的临床价值，以及 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 评估之间的这种新型整合将确定磷酸胆碱代谢作为 HCC 和慢性肝病诊断和治疗靶点的相对重要性，并增进我们对 HCC 发生和进展相关分子机制的了解。该提案是为了回应 NIH PA-08-243 而提交的。