Therapeutic modulation of a proteomic HCC risk signature with statins in patients with liver cirrhosis

他汀类药物对肝硬化患者蛋白质组 HCC 风险特征的治疗调节

• 批准号: 10853142
• 负责人: RAYMOND T CHUNG
• 金额: $ 36.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-25 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10853142
• 关键词: Biological Markers; Case/Control Studies; Characteristics; Chemoprevention; Cirrhosis; Clinical; Clinical Trials; Complication; Epigallocatechin Gallate; Erinaceidae; Erlotinib; Fright; Funding; Future; Goals; Guide prevention; Health; Incidence; Liver; Liver Cirrhosis; Longitudinal cohort study; Medical; Nature; Operative Surgical Procedures; Patients; Placebos; Prevention; Prevention therapy; Prevention trial; Primary carcinoma of the liver cells; Prognosis; Prospective cohort; Proteomics; Randomized, Controlled Trials; Recording of previous events; Recurrence; Refractory; Research Personnel; Retrospective Studies; Risk; Risk Marker; Sampling; Series; Serum; Signal Pathway; Signal Transduction; Surrogate Endpoint; Testing; Therapeutic; Validation; arm; atorvastatin; cancer chemoprevention; case control; clinical translation; cohort; hydrophilicity; improved; lipophilicity; mortality; novel strategies; preclinical study; prognostic; prospective; randomized, clinical trials; risk prediction; rosuvastatin

Hepatocellular carcinoma (HCC) is a major cirrhosis complication producing an alarming rise in mortality. The prognosis for HCC is poor due to extremely high recurrence rate even after curative-intent surgical therapies and limited efficacy of available medical therapies. Given its refractory nature, prevention of HCC in cirrhosis patients will be the most impactful strategy to improve its poor prognosis; however, effective HCC prevention remains a major unmet need. Retrospective and pre-clinical studies have suggested that statins are a viable form of HCC chemoprevention, with a differential effect between lipophilic and hydrophilic statins. Further evidence suggests that statins may modulate HCC risk through Hedgehog and Hippo signaling pathways. However, the clinical validation of statins has been hampered by the requirement for large and lengthy clinical trials to define their clinical utility. To overcome these challenges, we have developed a serum-based HCC risk biomarker, the Prognostic Liver Secretome signature (PLSec). Of note, PLSec is therapeutically modifiable and the magnitude of PLSec modulation is associated with future HCC incidence as demonstrated by our previous and preliminary studies. In a retrospective case-control series, PLSec-based HCC risk level was lower in cirrhosis patients on statins compared to non-users. Based on these observations, PLSec is now being tested as a surrogate endpoint in HCC chemoprevention trials of atorvastatin (TORCH trial). To achieve the goal of establishing statins as viable HCC chemoprevention with PLSec as a surrogate endpoint, we have assembled a team of cirrhosis and HCC experts to analyze serum samples from three nation-wide multi-center prospective cohorts (Liver Cirrhosis Network, Southern Liver Health Study, and Mass General Brigham cohorts) and two randomized controlled trials (TORCH and LCN RESCU trials). Aim 1. Validate lower biomarker-based HCC risk level in cirrhosis patients on statins compared to non-users. We will validate our preliminary finding in prospective case-control series of cirrhosis patients form the three cohorts. We will explore patient characteristics and types of statins associated with the PLSec-based HCC risk level, along with mechanistic markers of Hedgehog/Hippo signaling. Aim 2. Determine magnitude of biomarker-based HCC risk modulation after starting or stopping statins. We will conduct target trial emulation mimicking single-arm clinical trials with statins to determine the magnitude of PLSec modulation in patients who start or stop statins from three cohorts. We will explore patient characteristics and types of statins associated with PLSec-based HCC risk modulation, along with mechanistic markers. Aim 3. Compare biomarker-based HCC risk modulation between lipophilic and hydrophilic statins. We will compare the magnitude of placebo-adjusted PLSec modulation between lipophilic (atorvastatin) and hydrophilic (rosuvastatin) statins by analyzing serum samples from two parallel randomized clinical trials. We will explore patient characteristics associated with differential PLSec modulation, along with mechanistic markers. Our strategy showcases a novel approach to substantially advance clinical translation of HCC chemoprevention therapies.

肝细胞癌（HCC）是一种主要的肝硬化并发症，其死亡率惊人地上升。的