Early detection of HCC using noninvasive activity-based nanosensors

项目摘要/摘要 摘要肝细胞癌是最常见的原发性肝癌，起源于慢性肝脏。 疾病(CLD)，包括乙肝病毒(乙肝)、丙型肝炎病毒(丙型肝炎)、酒精性肝病(ALD)，以及 非酒精性脂肪性肝炎(NASH)如今，慢性肝病患者罹患肝细胞癌的风险很高，并受到监测。 与影像和血清生物标志物相近，但这些平台对早期肝细胞癌缺乏敏感性。 因此，尽管肝癌可以通过手术切除治愈，但在超过500,000人中，只有不到10%的人 由于诊断较晚，全世界每年新诊断的肝细胞癌患者都要接受手术切除。这 提案旨在开发GLUPSE肝脏测试(GLT)，这是一种基于活动的多重、可注射的诊断方法 探针，它检测驱动早期肝细胞癌病理特征的蛋白酶的活性。这些 无论病因如何，肝细胞癌特异性蛋白水解酶表达上调，它们的活性驱动基础肿瘤 包括血管生成、炎症和细胞外基质降解等过程。GLT平台对 早期肝细胞癌依靠两种信号放大机制；检测信号由 蛋白水解酶活性，通过酶的周转放大信号，并通过肾滤过浓缩到尿液中 用质谱仪进行定量。我们将确定与病因学无关的肝细胞癌蛋白水解酶并制定 人类使用的惰性聚合物支架上的GLT纳米传感器。然后，我们将验证GLT的检测能力 小鼠早期肝癌模型，包括主要病因、影像和血清基准 生物标志物，然后进行临床前毒理学研究，为IND提交做准备。GLT 与影像和血液生物标记物相比，为临床医生提供了对早期肝癌的快速和敏感的诊断。 GLT在早期阶段发现肝癌的能力将显著提高应答率(阶段为60%-70% 1)，每年从3万名患者死亡中拯救2万人的生命。对医疗保健系统的好处将是 超过4亿美元，基于增加根治性切除手术的数量，同时显著 减少肝脏移植的数量。GLT对肝细胞癌的影响将增加早期诊断 降低与治疗晚期肝癌相关的医疗成本，并最终改善患者 由于增加了医生的治疗选择而导致的结果。

Project Summary/Abstract Hepatocellular carcinoma (HCC) is the most common primary liver cancer and arises from chronic liver diseases (CLD) including hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic steatohepatitis (NASH). Today, patients with CLDs are at high risk for HCC and are monitored closely by imaging and serum biomarkers, but these platforms lack sensitivity for early stage HCC. Consequently, although HCC can be cured by surgical resection, less than 10% of the greater than 500,000 newly diagnosed HCC patients per year worldwide undergo surgical resection because of late diagnosis. This proposal aims to develop the Glympse liver test (GLT), a multiplexed, injectable diagnostic of activity-based probes, which detect the activity of proteases that drive the pathological hallmarks of early stage HCC. These HCC-specific proteases are upregulated regardless of etiology and their activities drive fundamental tumor processes including angiogenesis, inflammation, and ECM degradation. The GLT platform is ultrasensitive to early stage HCC by relying on two mechanisms for signal amplification; detection signals are generated by protease activity which amplifies signals by enzyme turnover, and are concentrated by renal filtration into urine for quantification by mass spectrometry. We will identify etiology independent HCC proteases and formulate GLT nanosensors on inert polymer scaffolds for human use. We will then validate the ability of GLT to detect early stage HCC in mouse models covering major etiologies, benchmarking against imaging and serum biomarkers, and then conduct preclinical toxicology studies in preparation for an IND submission. The GLT offers clinician a rapid and sensitive diagnosis of early stage HCC compared to imaging and blood biomarkers. The ability of GLT to detect HCC at an early stage will significantly improve response rates (60–70% at Stage 1), saving 20,000 lives from 30,000 patient deaths every year. The benefit to the healthcare system will be greater than $400 million based on increasing the number of curative resection surgeries while significantly reducing the number of liver transplants. The impact of the GLT for HCC will increase early stage diagnosis rates, reduce healthcare costs associated with treating late-stage HCC, and ultimately improve patient outcomes due to increased treatment options for physicians.