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，导致死亡率急剧上升。这 HCC 的预后很差，因为即使经过根治性手术治疗后，复发率也极高 现有药物疗法的疗效有限。鉴于其难治性，肝硬化患者中 HCC 的预防 将是改善其不良预后的最有影响力的策略；然而，有效的 HCC 预防仍然是一个 主要未满足的需求。回顾性和临床前研究表明他汀类药物是 HCC 的一种可行形式 化学预防，亲脂性和亲水性他汀类药物之间具有不同的作用。进一步的证据表明 他汀类药物可能通过 Hedgehog 和 Hippo 信号通路调节 HCC 风险。然而，临床 他汀类药物的验证受到了需要进行大规模、冗长的临床试验来定义其作用的阻碍。 临床实用性。为了克服这些挑战，我们开发了一种基于血清的 HCC 风险生物标志物，即 预后肝脏分泌蛋白组签名 (PLSec)。值得注意的是，PLSec 在治疗上是可修改的，并且其幅度 正如我们之前和初步的证明，PLSec 调制的程度与未来的 HCC 发病率相关 研究。在一项回顾性病例对照系列中，基于 PLSec 的肝硬化患者的 HCC 风险水平较低 他汀类药物与非使用者相比。根据这些观察结果，PLSec 现在正在作为替代端点进行测试 阿托伐他汀的 HCC 化学预防试验（T​​ORCH 试验）。实现确立他汀类药物可行的目标 以 PLSec 作为替代终点的 HCC 化学预防，我们组建了肝硬化和 HCC 团队 专家分析了三个全国多中心前瞻性队列的血清样本（肝硬化 网络、南方肝脏健康研究和麻省总医院布里格姆队列）和两项随机对照试验 （TORCH 和 LCN RESCU 试验）。目标 1. 验证肝硬化患者基于生物标志物的 HCC 风险水平较低 他汀类药物与非使用者相比。我们将在前瞻性病例对照系列中验证我们的初步发现 肝硬化患者分为三个队列。我们将探讨患者特征和相关的他汀类药物类型 具有基于 PLSec 的 HCC 风险水平，以及 Hedgehog/Hippo 信号传导的机制标记。目标2。 确定开始或停止他汀类药物后基于生物标志物的 HCC 风险调节的程度。我们将进行 目标试验模拟模仿他汀类药物的单臂临床试验以确定 PLSec 的程度 对三个队列中开始或停止他汀类药物的患者进行调节。我们将探索患者的特征并 与基于 PLSec 的 HCC 风险调节相关的他汀类药物类型以及机制标记。目标3。 比较亲脂性和亲水性他汀类药物之间基于生物标志物的 HCC 风险调节。我们将比较 亲脂性（阿托伐他汀）和亲水性（瑞舒伐他汀）之间安慰剂调整的 PLSec 调节幅度 他汀类药物通过分析两项平行随机临床试验的血清样本。我们将探索患者 与差分 PLSec 调制相关的特征以及机械标记。我们的策略 展示了一种显着推进 HCC 化学预防疗法临床转化的新方法。