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）是肝硬化的主要并发症，死亡率惊人地上升。的 HCC的预后很差，因为即使在治愈性手术治疗后， 现有药物治疗的疗效有限。鉴于其难治性，预防肝硬化患者中的HCC 将是改善其不良预后的最有效策略;然而，有效的HCC预防仍然是一个挑战。 未满足的重大需求。回顾性和临床前研究表明，他汀类药物是一种可行的肝癌形式 化学预防，亲脂性和亲水性他汀类药物之间的差异效应。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。但临床 他汀类药物的验证受到了大型和长期临床试验的要求的阻碍， 临床应用为了克服这些挑战，我们开发了一种基于血清的HCC风险生物标志物， 预后性肝分泌组特征（PLSec）。值得注意的是，PLSec是治疗上可修改的， PLSec调节与未来HCC发病率相关，正如我们先前和初步研究所证明的那样， 问题研究在一项回顾性病例对照研究中，肝硬化患者基于PLSec的HCC风险水平较低， 与非使用者相比。根据这些观察结果，PLSec目前正在作为替代终点进行测试 阿托伐他汀的HCC化学预防试验（TORCH试验）。为了实现将他汀类药物确立为可行药物的目标， 以PLSec作为替代终点的HCC化学预防，我们组建了一个肝硬化和HCC治疗团队， 专家分析来自三个全国性多中心前瞻性队列（肝硬化）的血清样本， 网络，南方肝脏健康研究和马萨诸塞州总布里格姆队列）和两项随机对照试验 （TORCH和LCN RESCU试验）。目标1.肝硬化患者中基于生物标志物的HCC风险水平更低， 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， 肝硬化患者形成三个组群。我们将探讨患者的特点和类型的他汀类药物相关 与基于PLSec的HCC风险水平，连同Hedgehog/Hippo信号传导的机制标志物一起沿着。目标2. 在开始或停止他汀类药物治疗后，确定基于生物标志物的HCC风险调节的程度。我们会进行 模拟他汀类药物单组临床试验的靶向试验仿真，以确定PLSec的大小 在三个队列中开始或停止他汀类药物治疗的患者中进行调节。我们将探索患者的特征， 与基于PLSec的HCC风险调节相关的他汀类药物类型，沿着机制标志物。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）之间安慰剂校正的PLSec调节幅度 他汀类药物通过分析来自两个平行随机临床试验的血清样本。我们将探索患者 与差异PLSec调制相关的特征，沿着机制标记。我们的战略 展示了一种新的方法，大大推进肝癌化学预防疗法的临床转化。