Non-invasive monitoring of metabolic liver cancer risk

无创监测代谢性肝癌风险

• 批准号: 10515278
• 负责人: Yujin Hoshida
• 金额: $ 20.35万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515278
• 关键词: Affect; Algorithms; Biological Assay; Biological Markers; CLIA certified; Cancer Etiology; Chemoprevention; Chronic; Cirrhosis; Clinical; Clinical Chemoprevention; Clinical Research; Clinical Trials; Companions; Data; Detection; Development; Diagnosis; Early Detection Research Network; Early Diagnosis; Enrollment; Epidemic; Erlotinib; Etiology; Future; Guidelines; Histologic; Incidence; Individual; Liver; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Medical; Metabolic; Metabolic Diseases; Monitor; Nested Case-Control Study; Overweight; Patients; Placebos; Population; Practice Guidelines; Primary carcinoma of the liver cells; Prognosis; Prospective cohort; Randomized; Resources; Risk; Sampling; Serum; Serum Proteins; Target Populations; Texas; Therapeutic; Time; Tumor Markers; Validation; Viral; adult obesity; alpha-Fetoproteins; arm; atorvastatin; base; cancer risk; cohort; cost effective; fatty liver disease; follow-up; improved; indexing; markov model; models and simulation; mortality; non-alcoholic fatty liver disease; non-invasive monitor; patient population; prognostic; prospective; risk prediction; screening; simulation; tumor

Hepatocellular carcinoma (HCC) prognosis remains dismal due to frequent diagnosis at late, non-curable stages. To improve early tumor detection, practice guidelines recommend semi-annual HCC screening in cirrhosis patients. However, the vast size of the cirrhosis population and the sharp rise of metabolic liver disease, i.e., non-alcoholic fatty liver disease (NAFLD) and newly proposed metabolic dysregulation- associated fatty liver disease (MAFLD) as the new dominant HCC etiology, poses a significant challenge in applying the guideline-recommended HCC screening to the entire target population. Thus, there is an urgent unmet need for biomarkers to predict future HCC risk to identify a subset of NAFLD/MAFLD patients who most need regular HCC screening and enable rational allocation of limited medical resources for the screening. Our previous simulation analysis showed that individual-risk-based personalized HCC screening is significantly more cost-effective than the current “one-size-fits-all” screening strategy. We previously developed a serum-protein-based etiology-agnostic Prognostic Liver Secretome signature (PLSec) to predict long-term HCC risk in general cirrhosis population, which is currently undergoing validation in prospectively collected national (NCI Early Detection Research Network [EDRN] Hepatocellular carcinoma Early Detection Strategy [HEDS]) and state-wide (Texas HCC Consortium [THCCC]) prospective cohorts with NCI support (R01CA222900, U01CA230694). PLSec is also incorporated as an endpoint in ongoing and planned HCC chemoprevention clinical trials to monitor therapeutic modulation of HCC risk level (NCT02273362, NCT04172779, NCT05028829). More recently, we have developed another serum-based biomarker specialized for NAFLD patients (PLSec-NAFLD) as an etiology-specific HCC risk biomarker with ongoing NCI support (R01CA233794) to further improve the PLSec-based HCC risk prediction in metabolic liver disease patients. Our preliminary data indeed suggest that combination of the etiology-agnostic (PLSec) and etiology-specific (PLSec-NAFLD) biomarkers, namely etiology-specific PLSec-NAFLD (etPLSec-NAFLD), improve HCC risk prediction in patients with metabolic liver disease, and also serve as companion biomarkers in HCC chemoprevention trial in metabolic liver disease patients. In this project, we will validate PLSec-NAFLD and etPLSec-NAFLD already available at our CLIA-certified UT Southwestern BioCenter to establish the biomarkers for future clinical trials and studies via the following Specific Aims: Aim 1. Validate the PLSec-NAFLD and etPLSec-NAFLD in NAFLD cirrhosis patients from the EDRN HEDS cohort. Aim 2. Validate the PLSec-NAFLD and etPLSec-NAFLD in MAFLD cirrhosis patients from the THCCC cohort. Aim 3. Evaluate therapeutic modulation of the PLSec-NAFLD in MAFLD cirrhosis patients.

肝细胞癌（HCC）的预后仍然令人沮丧，由于频繁的诊断晚，无法治愈， 阶段为了提高早期肿瘤检测，实践指南建议在2015年进行半年一次的HCC筛查。 肝硬化患者然而，肝硬化人群的庞大规模和代谢性肝病的急剧上升， 疾病，即，非酒精性脂肪肝（NAFLD）和新提出的代谢失调- 相关性脂肪肝（MAFLD）作为新的主要HCC病因，对 将指南推荐的HCC筛查应用于整个目标人群。因此，迫切需要 未满足的生物标志物需求，以预测未来的HCC风险，以确定NAFLD/MAFLD患者的子集， 需要定期进行HCC筛查，并能够合理分配有限的医疗资源用于筛查。我们 先前的模拟分析显示，基于个体风险的个性化HCC筛查显著 比目前“一刀切”的筛查策略更具成本效益。 我们先前开发了一种基于血清蛋白的病因不可知的预后性肝分泌组特征 （PLSec）预测一般肝硬化人群中的长期HCC风险，目前正在进行验证 在前瞻性收集的国家（NCI早期检测研究网络[EDRN]肝细胞癌 早期检测策略[HEDS]）和全州（德克萨斯州HCC联盟[THCCC]）前瞻性队列， NCI支持（R 01 CA 222900、U 01 CA 230694）。PLSec还被纳入为正在进行的和 计划进行HCC化学预防临床试验，以监测HCC风险水平的治疗调节 （NCT 02273362、NCT 04172779、NCT 05028829）。最近，我们开发了另一种基于血清的 NAFLD患者专用生物标志物（PLSec-NAFLD）作为病因特异性HCC风险生物标志物， 正在进行的NCI支持（R 01 CA 233794），以进一步改善代谢性疾病中基于PLSec的HCC风险预测 肝病患者。我们的初步数据确实表明，结合病因不可知（PLSec） 和病因特异性（PLSec-NAFLD）生物标志物，即病因特异性PLSec-NAFLD（etPLSec-NAFLD）， 改善代谢性肝病患者的HCC风险预测，也可作为伴随生物标志物 在代谢性肝病患者的HCC化学预防试验中。在这个项目中，我们将验证PLSec-NAFLD 和etPLSec-NAFLD已经在我们的CLIA认证的UT西南生物中心提供， 生物标志物用于未来的临床试验和研究，具体目的如下： 目标1。EDRN HEDS中NAFLD肝硬化患者的PLSec-NAFLD和etPLSec-NAFLD 队列。 目标二。研究THCCC队列中MAFLD肝硬化患者的PLSec-NAFLD和etPLSec-NAFLD。 目标3.评估MAFLD肝硬化患者中PLSec-NAFLD的治疗调节。