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

肝细胞癌是一种主要的肝硬变并发症，导致死亡率的惊人上升。这个 即使在根治性手术治疗后，由于极高的复发率，肝细胞癌的预后也很差 现有医学疗法的疗效有限。鉴于其难治性，预防肝硬化患者的肝细胞癌 将是改善其不良预后的最有效的策略；然而，有效的肝癌预防仍然是 未得到满足的主要需求。回顾和临床前研究表明，他汀类药物是肝癌的一种可行形式。 化学预防，具有亲脂性和亲水性他汀类药物的不同效果。进一步的证据表明 他汀类药物可能通过Hedgehog和Hippo信号通路调节肝细胞癌的风险。然而，临床上 他汀类药物的有效性一直受到限制，因为需要进行大规模而漫长的临床试验来确定其 临床应用。为了克服这些挑战，我们开发了一种基于血清的肝癌风险生物标记物 预后肝分泌体信号(PLSec)。值得注意的是，PLSec在治疗上是可修改的，其大小 PLSec的调节与未来的肝细胞癌的发病率有关，正如我们以前和初步的研究所证明的那样 学习。在一项回溯性病例对照系列研究中，基于PLSec的肝细胞癌风险水平较低。 他汀类药物与非使用者的比较。基于这些观察，PLSec现在正在作为代理端点进行测试 在阿托伐他汀的肝细胞癌化学预防试验(TORCH试验)中。为了实现建立他汀类药物可行的目标 肝细胞癌的化学预防以PLSec作为替代终点，我们已经组建了一个肝硬变和肝细胞癌的团队 专家分析来自全国三个多中心前瞻性队列(肝硬变)的血清样本 网络、南方肝脏健康研究和MASS General Brigham队列)和两个随机对照试验 (TORCH和LCN RESCU试验)。目的1.验证基于生物标记物的肝硬变患者较低的肝细胞癌风险水平 他汀类药物与非使用者的比较。我们将在未来的病例对照系列中验证我们的初步发现 肝硬变患者构成了这三个队列。我们将探索与他汀类药物相关的患者特征和类型 基于PLSec的肝癌风险水平，以及Hedgehog/Hippo信号的机械标记。目标2. 确定他汀类药物开始或停止后基于生物标记物的肝细胞癌风险调节的幅度。我们将进行 靶向试验模拟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服用他汀类药物的患者的调制。我们将探索患者的特征和 与基于PLSec的肝癌风险调节相关的他汀类药物类型，以及机械性标记物。目标3. 比较亲脂性和亲水性他汀类药物对基于生物标记物的肝癌风险的调节作用。我们将比较 安慰剂调节的PLSec在亲脂性(阿托伐他汀)和亲水性(瑞舒伐他汀)之间的调节幅度 通过分析来自两个平行随机临床试验的血清样本来研究他汀类药物。我们将探索病人 与差分PLSec调制相关的特征，以及机械标记。我们的战略 展示了一种新的方法，大大提高了肝细胞癌化学预防疗法的临床翻译。

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.