Methylation and Hepatocellular Carcinoma Outcomes

甲基化和肝细胞癌的结果

基本信息

批准号：
8702092
负责人：
Abby Brena Siegel
金额：
$ 17万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702092
关键词：
Affect Angiogenesis Inhibitors BAY 54-9085 Biological Biological Assay Biological Markers Blood CISH gene Cancer Center Cancer Etiology Cessation of life Child Clinical Core Facility DNA Methylation Development Diet Disease Epidemiology Erythrocytes Faculty Folate Future Gambling Gene Targeting Genes Goals Herbert Irving Comprehensive Cancer Center Immunohistochemistry Laboratories Lead MGMT gene MTHFR gene Malignant Neoplasms Medical center Methylation Molecular Oral Outcome Paraffin Pathologic Pathologist Pathology Pathway interactions Patient Selection Patients Peripheral Pharmaceutical Preparations Plasma Play Primary carcinoma of the liver cells Process Prognostic Marker Progression-Free Survivals Prospective Studies Public Health Questionnaires Recruitment Activity Resources Role Running Signal Pathway Site Systemic Therapy Tissues Toxic effect Tumor Suppressor Proteins Tumor Tissue Tyrosine Kinase Inhibitor United States Universities Vascular Endothelial Growth Factor Receptor cohort cost effective experience improved liver biopsy multidisciplinary novel peripheral blood promoter prospective pyrosequencing research study response tumor

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer death in the United States. Sorafenib, an oral tyrosine kinase inhibitor targeted against molecular signaling pathways including RAS and VEGFR, is the only systemic drug to date which has been shown to improve survival in advanced HCC. Biomarkers have not been well-studied in HCC. The goal of this proposal is to identify peripheral predictive and prognostic biomarkers related to DNA methylation in a prospective study of 200 advanced HCC patients, all treated with sorafenib. We will study a surrogate for global hypomethylation (LINE-1), and well as methylation of several gene sites thought to be involved in HCC development and progression. In particular, methylation of a particular tumor suppressor called RASSF1A has been shown to "turn on" other components of the RAS signaling pathway in HCC. Tumor expression of p-ERK, a downstream target in the RAS pathway, seems to correlate with better response to sorafenib. We will examine whether methylation of RASSF1A in plasma and tumor tissue correlates with p-ERK expression in tumor tissue. These experiments have the potential to identify simpler and safer ways to predict HCC outcomes. Finally, because of the possibility that folate may affect gene and global methylation levels, we will examine whether folate levels in plasma and red blood cells affect relationships between methylation status and outcome. Subjects will be recruited from the faculty practices at Columbia University and Weill-Cornell Medical Centers, given an epidemiologic questionnaire, and have blood drawn prior to starting sorafenib. Bloods will be processed on site, and assays will be run in the laboratory of Dr. Regina Santella, who directs the biomarker core facility of the Herbert Irving Comprehensive Cancer Center at Columbia. Folate levels will be processed by our collaborator at Columbia, Dr. Mary Gamble. In a subset of patients from Columbia we will also evaluate pathologic sections of tumor using immunohistochemistry and methylation assays. We will collaborate with both the Cancer Center's pathology core resource, together with Dr. Helen Remotti, an experienced GI pathologist, to complete these studies. This project will explore relationships between environmental, biological, and treatment-related effects on HCC outcomes in a multidisciplinary way. We believe the results will lead to the development of novel cost-effective predictive and prognostic biomarkers for those with this increasingly deadly disease.

描述（由申请人提供）：肝细胞癌（HCC）是美国癌症死亡的最快增加。索拉非尼（Sorafenib）是一种针对包括RAS和VEGFR在内的分子信号通路的口服酪氨酸激酶抑制剂，是迄今为止唯一的全身药物，已证明可以改善高级HCC的生存率。在HCC中，生物标志物尚未得到很好的研究。该提案的目的是在一项针对200名高级HCC患者的前瞻性研究中鉴定与DNA甲基化相关的外围预测性和预后生物标志物，均接受索拉非尼治疗。我们将研究全球低甲基化（线1）的替代物，以及被认为与HCC发育和进展有关的几个基因位点的甲基化。特别是，已证明称为RASSF1A的特定肿瘤抑制剂的甲基化可以“打开” HCC中RAS信号通路的其他成分。 P-ERK的肿瘤表达是RAS途径中的下游靶标，似乎与对索拉非尼的反应更好。我们将检查血浆中RASSF1A的甲基化和肿瘤组织中的甲基化是否与肿瘤组织中的P-ERK表达相关。这些实验有可能识别预测HCC结果的更简单，更安全的方法。最后，由于叶酸可能会影响基因和全球甲基化水平，因此我们将检查血浆和红细胞中的叶酸水平是否会影响甲基化状态和结果之间的关系。受试者将从哥伦比亚大学的教师实践和威尔康尔医疗中心招募，并给予流行病学问卷，并在开始索拉非尼之前抽血。血液将在现场进行处理，分析将在Regina Santella博士的实验室中进行，后者指导哥伦比亚赫伯特·欧文（Herbert Irving）综合癌症中心的生物标志物核心设施。叶酸水平将由我们的哥伦比亚合作者Mary Gamble博士处理。在哥伦比亚的一部分患者中，我们还将使用免疫组织化学和甲基化测定法评估肿瘤的病理切片。我们将与经验丰富的GI病理学家Helen Remotti博士一起与癌症中心的病理核心资源合作，以完成这些研究。该项目将以多学科的方式探索环境，生物学和与治疗相关的影响对HCC结果之间的关系。我们认为，结果将导致对这种日益致命疾病的人的新型具有成本效益的预测性和预后生物标志物的发展。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.

核糖核苷酸还原酶抑制剂 3-氨基吡啶-2-甲醛缩氨基硫脲联合吉西他滨治疗晚期胆道癌患者的 II 期试验。

DOI：
10.1007/s00280-010-1481-z
发表时间：
2011
期刊：
Cancer chemotherapy and pharmacology
影响因子：
3
作者：
Ocean,AllysonJ;Christos,Paul;Sparano,JosephA;Matulich,Dan;Kaubish,Andreas;Siegel,Abby;Sung,Max;Ward,MaureenM;Hamel,Nancy;Espinoza-Delgado,Igor;Yen,Yun;Lane,MaureenE
通讯作者：
Lane,MaureenE

Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients.

DOI：
10.1159/000367971
发表时间：
2015
期刊：
Oncology
影响因子：
3.5
作者：
Siegel AB;Goyal A;Salomao M;Wang S;Lee V;Hsu C;Rodriguez R;Hershman DL;Brown RS Jr;Neugut AI;Emond J;Kato T;Samstein B;Faleck D;Karagozian R
通讯作者：
Karagozian R

Milk thistle: early seeds of potential.

水飞蓟：潜力的早期种子。