Non-invasive monitoring of metabolic liver cancer risk

肝细胞癌(肝细胞癌)的预后仍然很差，因为经常在晚期确诊，无法治愈。 各阶段。为了改善肿瘤的早期检测，实践指南建议在#年进行半年一次的肝癌筛查 肝硬变患者。然而，肝硬变人群的庞大规模和代谢性肝脏的急剧上升 疾病，即非酒精性脂肪性肝病(NAFLD)和新提出的代谢失调- 相关性脂肪性肝病(MAFLD)作为新的主导的肝细胞癌病因，在 将指南推荐的肝细胞癌筛查应用于整个目标人群。因此，有一个紧急的 预测未来肝癌风险的生物标记物未得到满足的需求，以确定最多的NAFLD/MAFLD患者子集 需要定期进行肝细胞癌筛查，并合理分配有限的医疗资源进行筛查。我们的 以往的模拟分析表明，基于个体风险的个性化肝癌筛查具有显著的 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学-不可知的预后肝分泌组征象。 (PLSec)预测一般肝硬变人群的长期肝癌风险，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 早期检测战略[HEDS])和全州范围(德克萨斯州肝癌联盟[THCCC])的预期队列 NCI支持(R01CA222900、U01CA230694)。PLSec也被合并为正在进行的和 计划中的肝细胞癌化学预防临床试验以监测对肝细胞癌风险水平的治疗调节 (NCT02273362、NCT04172779、NCT05028829)。最近，我们开发了另一种基于血清的 NAFLD患者特异性生物标记物(PLSec-NAFLD)作为病因特异性肝癌风险生物标记物 持续的NCI支持(R01CA233794)，以进一步改进基于PLSec的代谢领域的肝癌风险预测 肝病患者。我们的初步数据确实表明，病因学-不可知论(PLSec)的组合 和病原学特异性(PLSec-NAFLD)生物标志物，即病原学特异性PLSec-NAFLD(etPLSec-NAFLD)， 改善代谢性肝病患者的肝细胞癌风险预测，并作为伴生生物标记物 在代谢性肝病患者的肝细胞癌化学预防试验中。在本项目中，我们将验证PLSec-NAFLD 和etPLSec-NAFLD已经在我们的CLIA认证的德克萨斯大学西南生物中心提供，以建立 通过以下具体目标为未来的临床试验和研究提供生物标志物： 目的1.从EDRN HEDS验证PLSec-NAFLD和etPLSec-NAFLD在NAFLD肝硬变患者中的有效性 一群人。 目的2.验证PLSec-NAFLD和etPLSec-NAFLD在THCCC队列MAFLD肝硬变患者中的有效性。 目的3.评价PLSec-NAFLD对MAFLD肝硬变患者的疗效调节作用。

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.