Functional Genomics and Molecular Imaging of Liver Disease and Cancer

描述（由申请人提供）：HCC是世界上第四大最常见的癌症，也是世界上第三大癌症死亡原因。在美国，HCC的发病率持续上升，2010年估计有24120例新确诊病例。即使在早期，这种疾病的预后也很差，5年生存率为26%，而转移时只有2%。手术被认为是肝细胞癌的最佳治疗选择，但前提是疾病早期发现且未转移。不幸的是，目前肝细胞癌（HCC）的影像学策略倾向于低估疾病负担和范围，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患者也有潜在的肝纤维化或肝硬化，残肝的健康状况是决定手术是否可耐受的重要因素。影像学在评估或预测被认为需要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，影像学在预测或监测HCC对治疗剂的反应方面尚未找到一席之地。美国国立卫生研究院肝病研究行动计划呼吁开发可用于HCC和慢性肝病临床的新成像技术，并已确定正电子发射断层扫描（PET）是一种有前途的技术，可以解决其中的一些问题。不受调节的胆碱合成是在许多癌症中发现的一个特征，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。然而，目前尚不确定胆碱磷脂代谢的变化是由于膜磷脂需求的增加还是由于有丝分裂信号的增加，因为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。利用正电子发射断层扫描（PET）和正在研究的胆碱激酶示踪底物[18F]-氟甲基胆碱（FCH），在增强肿瘤磷胆碱合成的基础上检测原发性和转移性HCC是可行的。然而，FCH PET对HCC的总体准确性尚未得到正式测试，导致胆碱激酶上调的分子机制在HCC中仍未确定。拟议项目的目的是：1)收集新鲜冷冻肝组织标本进行影像学-病理相关性研究，与FCH PET/CT进行相关性研究，评价其作为HCC肝脏成像方式的诊断价值；2)纵向评估HCC幸存者的肝功能和疾病结局，评价FCH PET/CT作为肝细胞功能指标的临床价值和肝癌手术切除时获得的转录特征的预后价值。这种功能基因组学与FCH PET/CT评估之间的新整合将确定磷脂代谢作为HCC和慢性肝病诊断和治疗靶点的相对重要性，并推进我们对HCC发生和进展相关的分子机制的了解。本提案是根据NIH PA-08-243提交的。

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.