Functional Genomics and Molecular Imaging of Liver Disease and Cancer

描述（由申请人提供）：HCC是世界上第四大常见癌症，也是世界范围内第三大癌症死亡原因。在美国，HCC发病率持续增加，2010年估计诊断出24，120例新病例。即使在早期阶段，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，但只有在疾病被早期发现并且没有转移的情况下。不幸的是，目前肝细胞癌（HCC）的成像策略往往低估了疾病的负担和程度，使那些不是真正手术候选人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，残肝的健康在决定手术是否耐受方面很重要。影像学在评估或预测被认为是手术候选人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HCC分子治疗（如索拉非尼）的出现，成像尚未在预测或监测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新的成像技术，可以在临床上应用于HCC和慢性肝病，并已确定正电子发射断层扫描（PET）作为一种有前途的技术，可以解决其中一些问题。不受调节的磷酸胆碱合成是在许多癌症中发现的特征，也在HCC中观察到。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对膜磷脂的需求增加还是促有丝分裂信号传导的增加，因为磷酸胆碱既是膜磷脂，也是Ras介导的促有丝分裂途径如MAPK和PI 3 K-AKT-mTOR途径中的重要第二信使。在增强肿瘤磷酸胆碱合成的基础上检测原发性和转移性HCC是可行的，使用正电子发射断层扫描（PET）与胆碱激酶的研究示踪底物，[18 F]-氟甲基胆碱（FCH）。然而，FCH PET用于HCC的总体准确性尚未得到正式测试，并且导致HCC胆碱激酶上调的分子机制仍未确定。拟议项目的目的是：1）进行放射学-病理学相关性研究，收集新鲜冷冻肝组织标本用于与FCH PET/CT的相关性，以评估其作为HCC的肝脏成像模式的诊断性能，2）纵向评估HCC幸存者的肝功能和疾病结局，以评估FCH PET/MRI的临床价值。CT作为肝细胞功能的量度和HCC手术切除时获得的转录特征的预后价值。功能基因组学和FCH PET/CT评估之间的这种新的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，并推进我们对HCC发生和进展相关分子机制的认识。本提案是针对NIH PA-08-243提交的。 公共卫生相关性：改变的胆碱磷脂代谢是最近公认的癌症标志，其被评估为许多癌症（包括肝细胞癌（HCC））中的潜在诊断和治疗靶点。使用正电子发射断层扫描/计算机断层扫描（PET/CT）和研究示踪剂化合物[18 F]氟胆碱（FCH），已经证明了在体内测量胆碱磷酸化率的基础上检测HCC的可行性。建议以肿瘤组织病理学作为参考的金标准，对接受手术切除治疗的HCC患者进行FCH PET/CT诊断性能的正式评价。由于导致肿瘤中胆碱代谢增强的分子信号改变目前尚未完全阐明，因此该提案包括一项新计划，将收集的冷冻组织标本的全基因组基因表达谱结合起来，以确定与HCC中胆碱代谢改变相关的基因和信号转导途径。预期的结果不仅将提供一个生物学解释如何以及为什么PET成像作为一种诊断肝癌的方式，但也推进了我们的胆碱代谢在肝癌进展和转移的作用的理解。基因组结果反过来可能导致新的生物标志物特征，用于早期诊断HCC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化的进展而下降，该项目还将评估FCH PET/CT作为肝细胞功能的标志物，可能导致疾病监测，手术治疗计划和临床试验风险分层的新应用。

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.