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: 8163515
• 负责人: Sandi Alexander Kwee
• 金额: $ 45.2万
• 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/8163515
• 关键词: Accounting; Address; BAY 54-9085; Biological; Biological Markers; Cancer Detection; Cancer Etiology; Cell membrane; Characteristics; Choline; Choline Kinase; Chronic; 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; 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; Pattern; 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; Screening procedure; 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; 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; 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. PUBLIC HEALTH RELEVANCE: Altered choline phospholipid metabolism is a recently recognized hallmark of cancer that is being evaluated as a potential diagnostic and therapeutic target in a number of cancers, including hepatocellular carcinoma (HCC). The feasibility of detecting HCC on the basis of measuring the phosphorylation rate of choline in-vivo has been shown using positron emission tomography/computed tomography (PET/CT) and the investigational tracer compound [18F] fluorocholine (FCH). A formal evaluation of the diagnostic performance of FCH PET/CT in patients undergoing surgical resection as treatment for HCC is proposed using tumor histopathology as the gold standard of reference. Since the molecular signaling alterations leading to enhanced choline metabolism in tumors are not fully elucidated at this time, this proposal includes a novel plan to incorporate whole-genome gene expression profiling of the frozen tissue specimens being collected to identify the genes and signal transduction pathways related to altered choline metabolism in HCC. The expected results will not only provide a biological explanation of how and why PET imaging works as a diagnostic modality for HCC, but also advance our understanding of the role of choline metabolism in HCC progression and metastasis. The genomic results in turn could lead to novel biomarker signatures for early diagnosis of HCC and new targets for drug therapy. Furthermore, because hepatic choline metabolism declines with the progression of chronic liver disease and cirrhosis, this project will also evaluate FCH PET/CT as a marker of hepatocyte function, potentially leading to novel applications in disease surveillance, surgical treatment planning, and clinical trial risk stratification.

描述(申请人提供)：肝癌是世界上第四大常见癌症，也是全球癌症死亡的第三大原因。在美国，肝细胞癌的发病率继续上升，2010年估计有24,120例新确诊病例。即使在早期，这种疾病的预后也很差，5年存活率为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，但前提是这种疾病必须及早发现并且没有转移。不幸的是，目前肝细胞癌的成像策略有低估疾病负担和程度的趋势，使不是真正适合手术的患者暴露在不必要的发病率、风险和费用之下。许多肝细胞癌患者还存在潜在的肝纤维化或肝硬变，残肝的健康状况是决定手术能否耐受的重要因素。在评估或预测被认为是手术对象的患者的残余肝功能方面，成像也没有发挥足够的作用。此外，随着分子疗法如索拉非尼的出现，成像还没有在预测或监测肝细胞癌对治疗药物的反应中找到一席之地。NIH肝病研究行动计划呼吁开发可应用于临床的新的成像技术，并已确定正电子发射断层扫描(PET)是一项有望解决其中一些问题的技术。无调控的磷胆碱合成是在许多癌症中发现的一个特征，在肝细胞癌中也观察到了这种特征。它是正在开发的一些新的诊断和治疗策略的目标。然而，目前尚不能确定胆碱磷脂代谢的变化是由于对膜磷脂需求的增加还是由于有丝分裂信号的增加，因为磷胆碱既是膜磷脂又是RAS介导的有丝分裂途径(如MAPK和PI3K-AKT-mTOR途径)中重要的第二信使。以[18F]-氟甲基胆碱(FCH)为示踪底物，利用正电子发射断层扫描(PET)技术，在增强的肿瘤磷胆碱合成的基础上检测原发性和转移性肝细胞癌是可行的。然而，FCHPET对肝细胞癌的总体准确性尚未得到正式测试，导致胆碱激酶上调的分子机制在肝细胞癌仍未确定。该项目的目的是：1)进行放射病理学相关性研究，收集新鲜的冷冻肝组织标本，与FCH PET/CT对照，以评估其作为肝细胞癌的肝脏成像手段的诊断性能；2)纵向评估肝细胞癌存活者的肝功能和疾病转归，以评估FCH PET/CT作为衡量肝细胞功能的临床价值和在手术切除肝细胞时获得的转录信号的预后价值。这种功能基因组学与FCHPET/CT评估的新整合将确定磷胆碱代谢作为肝癌和慢性肝病诊断和治疗靶点的相对重要性，并促进我们对与肝癌发生和发展相关的分子机制的了解。本提案是根据NIH PA-08-243的要求提交的。 公共卫生相关性：胆碱磷脂代谢改变是最近公认的癌症的一个特征，正在被评估为包括肝细胞癌(HCC)在内的许多癌症的潜在诊断和治疗靶点。用正电子发射断层扫描/计算机断层扫描(PET/CT)和正在研究的示踪化合物[18F]氟胆碱(FCH)证明了通过测量体内胆碱的磷酸化速率来检测肝癌的可行性。建议以肿瘤组织病理学为金标准，对接受手术切除的肝细胞癌患者的FCHPET/CT诊断性能进行正式评估。由于导致肿瘤胆碱代谢增强的分子信号改变目前还没有完全阐明，这一建议包括一个新的计划，包括收集冰冻组织标本的全基因组基因表达谱，以确定与肝细胞癌胆碱代谢改变相关的基因和信号转导途径。预期的结果不仅将为PET成像作为肝癌诊断手段的方式和原因提供生物学解释，而且还将促进我们对胆碱代谢在肝癌进展和转移中的作用的理解。基因组学结果反过来可能导致新的生物标记物签名，用于肝细胞癌的早期诊断和药物治疗的新靶点。此外，由于肝脏胆碱代谢随着慢性肝病和肝硬变的进展而下降，该项目还将评估FCH PET/CT作为肝细胞功能的标志，可能导致在疾病监测、外科治疗计划和临床试验风险分层方面的新应用。