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，导致死亡率令人震惊。这 即使经过治愈的手术疗法，HCC的预后也很差，因此复发率极高。 可用的医疗疗法有限的功效。鉴于其难治性，预防肝硬化患者的HCC 将是改善其预后不良的最有影响力的策略；但是，有效的HCC预防仍然是 主要的未满足需求。回顾性和临床前研究表明他汀类药物是HCC的可行形式 化学预防，在亲脂性和亲水性汀类药物之间具有差异作用。进一步的证据表明 他汀类药物可以通过刺猬和河马信号通路调节HCC风险。但是，临床 他汀类药物的验证受到了对大型且冗长的临床试验的要求，以定义其 临床实用程序。为了克服这些挑战，我们开发了基于血清的HCC风险生物标志物， 预后肝脏分泌签名（PLSEC）。值得注意的是，PLSEC在治疗上是可修改的，大小 PLSEC调制与未来的HCC发病率有关，如我们以前的和初步 研究。在回顾性病例对照系列中，基于PLSEC的HCC风险水平较低 他汀类药物与非用户相比。基于这些观察结果，PLSEC现在被测试为替代端点 在HCC Atorvastatin的HCC化学预防试验中（火炬试验）。实现将他汀类药物确立为可行的目标 与PLSEC作为替代端点的HCC化学预防，我们组装了一支cirhosos和HCC团队 专家分析来自三个全国性多中心前瞻性队列的血清样品（肝硬化 网络，南部肝脏健康研究和大规模杨百翰群岛）和两项随机对照试验 （火炬和LCN救援试验）。 AIM 1。验证肝硬化患者的基于生物标志物的较低的HCC风险水平 他汀类药物与非用户相比。我们将在预期的病例对照系列中验证我们的初步发现 肝硬化患者组成三个队列。我们将探索患者特征和汀类药物的类型 具有基于PLSEC的HCC风险水平，以及Hedgehog/Hippo信号传导的机械标记。目标2。 开始或停止他汀类药物后，确定基于生物标志物的HCC风险调节的大小。我们将进行 目标试验仿真模仿他汀类药物的单臂临床试验以确定PLSEC的大小 从三个队列开始或停止他汀类药物的患者的调节。我们将探索患者特征和 与基于PLSEC的HCC风险调制以及机械标记相关的他汀类药物的类型。目标3。 比较基于生物标志物的HCC风险调节亲脂性汀类药物之间的风险调节。我们将比较 安慰剂调整后的PLSEC调制的幅度（atorvastatin）和亲水性（rosuvastatin）之间 他汀类药物通过分析来自两个平行的随机临床试验的血清样品。我们将探索病人 与差分PLSEC调制以及机械标记相关的特征。我们的策略 展示了一种新的方法，可以实质性地推进HCC化学预防疗法的临床翻译。