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
基本信息
- 批准号:10853142
- 负责人:
- 金额:$ 36.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Biological MarkersCase/Control StudiesCharacteristicsChemopreventionCirrhosisClinicalClinical TrialsComplicationEpigallocatechin GallateErinaceidaeErlotinibFrightFundingFutureGoalsGuide preventionHealthIncidenceLiverLiver CirrhosisLongitudinal cohort studyMedicalNatureOperative Surgical ProceduresPatientsPlacebosPreventionPrevention therapyPrevention trialPrimary carcinoma of the liver cellsPrognosisProspective cohortProteomicsRandomized, Controlled TrialsRecording of previous eventsRecurrenceRefractoryResearch PersonnelRetrospective StudiesRiskRisk MarkerSamplingSeriesSerumSignal PathwaySignal TransductionSurrogate EndpointTestingTherapeuticValidationarmatorvastatincancer chemopreventioncase controlclinical translationcohorthydrophilicityimprovedlipophilicitymortalitynovel strategiespreclinical studyprognosticprospectiverandomized, clinical trialsrisk predictionrosuvastatin
项目摘要
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
项目成果
期刊论文数量(0)
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{{ truncateString('RAYMOND T CHUNG', 18)}}的其他基金
YAP signaling in the pathogenesis of NAFLD in people living with HIV
HIV 感染者 NAFLD 发病机制中的 YAP 信号传导
- 批准号:
10809266 - 财政年份:2023
- 资助金额:
$ 36.67万 - 项目类别:
Trial of Statins for Chemoprevention in Hepatocellular Carcinoma
他汀类药物用于肝细胞癌化学预防的试验
- 批准号:
10297899 - 财政年份:2021
- 资助金额:
$ 36.67万 - 项目类别:
Trial of Statins for Chemoprevention in Hepatocellular Carcinoma
他汀类药物用于肝细胞癌化学预防的试验
- 批准号:
10478274 - 财政年份:2021
- 资助金额:
$ 36.67万 - 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
- 批准号:
10170260 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
- 批准号:
10388224 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
- 批准号:
10217038 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
Immunologic correlates of functional cure of HBV with immune checkpoint blockade
乙型肝炎功能性治愈与免疫检查点阻断的免疫学相关性
- 批准号:
10624243 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
- 批准号:
10082973 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
Cooperative mechanisms of HIV-enhanced liver fibrogenesis in HBV Coinfection
HBV 合并感染中 HIV 增强肝纤维化的协同机制
- 批准号:
10426106 - 财政年份:2020
- 资助金额:
$ 36.67万 - 项目类别:
HIV, HCV, Hippo, and Liver Disease Progression
HIV、HCV、Hippo 和肝病进展
- 批准号:
10303053 - 财政年份:2017
- 资助金额:
$ 36.67万 - 项目类别:
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