Evaluation of treatment predictors reflecting beta-catenin activation in hepatocellular carcinoma

项目概要/摘要 肝细胞癌（HCC）是全世界癌症死亡率的主要原因，其发病率为20%。 在美国的男性和女性中都在上升。抗PD 1和抗PD-L1免疫检查点抑制剂（ICI） 目前FDA已批准抗体用于晚期HCC，然而，只有20%的患者接受这些药物治疗， 会对治疗有客观反应因为免疫相关的不良事件是不平凡的，预测 需要能够解释免疫治疗反应的可变性的生物标志物来优化患者选择。 最近几条研究路线已经会聚到将Wnt/β的致癌激活与Wnt/β的致癌激活相关联。 在HCC中，catenin信号通路与肿瘤免疫逃避和对ICI治疗的不良临床反应有关。在 以前的研究，我们发现HCC表现出高摄取的正电子发射断层扫描/计算机 断层扫描（PET/CT）显像剂18F-氟胆碱（FCH）常属于分子肿瘤亚型 与β-连环蛋白激活和免疫回避有关。基于靶向测序的液体活检 无细胞DNA（cfDNA）也使识别携带突变的肿瘤患者成为可能 与增加的Wnt/β-连环蛋白信号传导相关。 该项目包括一项2期生物标志物临床试验，以前瞻性地评估这些特定的 PET/CT和液体活组织检查作为用于基于以下检测对ICI治疗无效的HCC的工具的实施例： β-连环蛋白激活。除了表征和比较FCH PET/CT的预测能力外， 和cfDNA突变分析，该项目将利用基于决策树的 机器学习来估计整合成像-基因组生物标志物的预测性能，同时还 进一步研究肿瘤突变如何与PET代谢表型和免疫治疗反应相关。 此外，由于肿瘤18F-氟脱氧葡萄糖（FDG）摄取与HCC中FCH摄取不一致， 第三个目标将利用该试验作为分子筛选过程，以创建一个富集的患者子队列， FDG-avid肿瘤。这些患者将接受系列FDG PET/CT，以评估FDG作为预测性 HCC的正交分子亚型的ICI反应的生物标志物。如果发现这些诊断测试 在预测肿瘤抗性/反应方面是可靠的，它们可以显著提高临床精确度， 免疫疗法对HCC和可能的其他癌症的总体益处。

PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide and its incidence is rising in both men and women in the United States. Anti-PD1 and anti-PD-L1 immune checkpoint inhibitor (ICI) antibodies are now FDA approved for advanced HCC, however, as few as 20% of patients receiving these agents will show an objective response to therapy. Because immune-related adverse events are non-trivial, predictive biomarkers that can explain the variability in immunotherapy response are needed to optimize patient selection. Several lines of research have recently converged to associate oncogenic activation of the Wnt/beta- catenin signaling pathway with tumor immune-evasion and poor clinical response to ICI therapy in HCC. In previous research, we found that HCC exhibiting high uptake of the positron emission tomography / computed tomography (PET/CT) imaging agent 18F- fluorocholine (FCH) often belonged to molecular tumor sub-types associated with beta-catenin activation and immune avoidance. Liquid biopsy based on targeted sequencing of cell-free DNA (cfDNA) has also made it possible to identify patients who have tumors that harbor mutations associated with increased Wnt/beta-catenin signaling. This project comprises a phase 2 biomarker clinical trial to prospectively evaluate these specific embodiments of PET/CT and liquid biopsy as tools for detecting HCC recalcitrant to ICI therapy on the basis of beta-catenin activation. In addition to characterizing and comparing the predictive capabilities of FCH PET/CT and cfDNA mutation profiling based on phase 2 clinical endpoints, this project will utilize decision tree based machine learning to estimate the predictive performance of an integrative imaging-genomic biomarker while also further examining how tumor mutations are related to PET metabolic phenotype and immunotherapy response. Furthermore, because tumor 18F-fluorodeoxyglucose (FDG) uptake is incongruent with FCH uptake in HCC, a third aim will utilize the trial as a molecular screening process to create an enriched sub-cohort of patients with FDG-avid tumors. These patients will undergo serial FDG PET/CT to evaluate FDG as a source of predictive biomarkers of ICI response for an orthogonal molecular sub-type of HCC. If these diagnostic tests are found reliable at predicting tumor resistance/response, they could significantly enhance the clinical precision and overall benefit of immunotherapy for HCC and possibly other cancers.