Novel circulating biomarker digital scores for assessing treatment response in liver cancer

项目总结/摘要 肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。当地 消融和经动脉化疗栓塞（TACE）是HCC最常用的治疗方式。 治疗后，患者接受放射学成像以评价治疗反应。评估 由于治疗相关的非特异性变化，对局部消融或TACE的治疗反应通常具有挑战性 并且明确的评估通常需要重复的横截面成像。同样，也有穷人。 治疗后肿瘤活力的放射学-组织学相关性，在38%的HCC中观察到不一致的结果 局部消融或TACE后的患者。虽然血清甲胎蛋白（AFP）可以帮助评估治疗 然而，只有不到一半的HCC患者在治疗前AFP升高。这限制了它的效用 更广泛的实施。该R21提案的主要目的是研究新型的 用于评估HCC治疗反应的循环生物标志物数字评分。 最近，Zhu博士（PI）和Tseng博士（合作研究者）开发了一种精简的细胞外HCC 囊泡（EV）数字评分测定，其结合了两种稳健的技术，即，EV Click芯片用于纯化 HCC EV和用于定量HCC特异性mRNA的逆转录液滴数字PCR（RT-ddPCR） 这些标记物在早期HCC检测中具有出色的性能。此外，杨医生（联系PI） 证明了GALAD评分，来自三种HCC蛋白质肿瘤标志物（AFP-L3，AFP和Des- 羧基凝血酶原）对于早期HCC的检测是高度准确的。两项评分均反映肿瘤负荷 我们的试验数据显示，它们在评估治疗反应方面的表现很有希望。因此，中央 该R21建议假设是治疗前和治疗后HCC EV数字评分、GALAD评分 两个独立分数的积分（即，HCC EV-GALAD数字评分）可以评估HCC治疗 反应杨博士和朱博士将进行生物标志物研究来验证这一假设。这个项目是创新的 因为它利用了两个正交的生物标志物评分;一个新的HCC EV数字评分和有前途的血清蛋白- 基于score这项R21提案的长期目标是确定HCC EV、GALAD、 和HCC EV-GALAD数字评分，用于评估HCC治疗反应，并验证其在以下方面的性能： 一个独立的群体。

PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Local ablation and transarterial chemoembolization (TACE) are the most commonly used treatment modality for HCC. Following treatment, patients undergo radiologic imaging for evaluation of treatment response. Assessing treatment response to local ablation or TACE is often challenging due to treatment-related nonspecific changes and definitive assessment typically requires repeated cross-sectional imaging. Similarly, there is poor radiologic-histological correlation of post-treatment tumor viability, with discordant results seen in 38% of HCC patients after local ablation or TACE. While serum alpha-fetoprotein (AFP) can aid in assessing treatment response, less than half of all patients with HCC have an elevated AFP before treatment. This limits its utility for broader implementation. The main objective of this R21 proposal is to investigate the performance of novel circulating biomarker digital scores for evaluation of HCC treatment response. Recently, Drs. Zhu (PI) and Tseng (co-Investigator) has developed a streamlined HCC extracellular vesicles (EV) digital scoring assay that couples two robust technologies, i.e., EV Click Chip for purification of HCC EVs and reverse-transcription droplet digital PCR (RT-ddPCR) for quantification of HCC-specific mRNA markers with outstanding performance for early-stage HCC detection. Besides, Dr. Yang (contact-PI) demonstrated that the GALAD score, derived from three HCC protein tumor markers (AFP-L3, AFP, and Des- carboxyprothrombin) is highly accurate for the detection of early-stage HCC. Both scores reflect tumor burden and our pilot data showed their promising performance in assessing treatment response. Thus, the central hypothesis of this R21 proposal is that pre- and post-treatment HCC EV digital score, GALAD score, and integration of two independent scores (i.e., HCC EV-GALAD digital score) can evaluate HCC treatment response. Dr. Yang and Dr. Zhu will conduct biomarker studies to test the hypothesis. This project is innovative as it leverages two orthogonal biomarker scores; a novel HCC EV digital score and promising serum protein- based score. The long-term goal of this R21 proposal is to determine the performance of HCC EV, GALAD, and HCC EV-GALAD digital scores for evaluating HCC treatment response and validate their performance in an independent cohort.