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

反映肝细胞癌β-连环蛋白激活的治疗预测因子的评估

• 批准号: 10277385
• 负责人: Sandi Alexander Kwee
• 金额: $ 52万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277385
• 关键词: Biological Markers; Cancer Etiology; Cells; Cessation of life; Characteristics; Classification; Clinic; Clinical; Clinical Trials; Communication; DNA Sequence Alteration; DNA sequencing; Decision Trees; Detection; Diagnostic; Diagnostic tests; Effectiveness; Emission-Computed Tomography; Evaluation; Exhibits; FDA approved; Genes; Genetic Engineering; Genetic Transcription; Goals; Image; Immune; Immune checkpoint inhibitor; Immunotherapy; Incidence; Individual; Induced Mutation; Learning; Ligands; Machine Learning; Malignant Neoplasms; Maps; Metabolic; Microsatellite Instability; Minority; Missense Mutation; Modeling; Molecular; Mutate; Mutation; Odds Ratio; Oncogenic; Outcome; Participant; Pathway interactions; Patient Selection; Patients; Performance; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Positron-Emission Tomography; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Process; Proteins; Refractory; Reporting; Research; Resistance; Signal Pathway; Signal Transduction; Source; Testing; Transcription Coactivator; Transcriptional Activation; Treatment outcome; Tumor Escape; Tumor Markers; United States; Woman; X-Ray Computed Tomography; advanced disease; anti-PD-1; anti-PD-L1; antibody inhibitor; base; beta catenin; blood-based biomarker; cancer therapy; cell free DNA; checkpoint therapy; clinical diagnostics; clinical predictors; cohort; determinants of treatment resistance; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; genomic biomarker; imaging agent; imaging biomarker; immune-related adverse events; improved; liquid biopsy; melanoma; men; metabolic phenotype; migration; molecular subtypes; mortality; mutational status; neoplastic cell; next generation sequencing; objective response rate; predictive marker; predictive tools; programmed cell death ligand 1; programmed cell death protein 1; programs; prospective; response; screening; targeted sequencing; tool; transcriptomics; tumor; tumor DNA; tumor microenvironment; tumor progression; uptake

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.

项目摘要/摘要 肝细胞癌是全球癌症死亡的主要原因，其发病率为 在美国，男性和女性的比例都在上升。抗PD1和抗PD-L1免疫检查点抑制物(ICI) 然而，现在FDA批准抗体用于晚期肝癌，只有20%的患者接受这些药物治疗 会表现出对治疗的客观反应。因为免疫相关的不良事件不是无关紧要的、可预测的 为了优化患者选择，需要能够解释免疫治疗反应变异性的生物标记物。 最近，几个研究方向汇聚在一起，将Wnt/beta-1的致癌激活联系在一起。 连环蛋白信号通路与肿瘤免疫逃逸和肝细胞癌ICI治疗的不良临床反应。在……里面 以前的研究，我们发现肝细胞癌表现出高摄取正电子发射断层扫描/计算机 体层摄影术(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 无细胞脱氧核糖核酸(Cfdna)也使识别携带突变的肿瘤患者成为可能。 与Wnt/β-catenin信号的增加有关。 该项目包括2期生物标记物临床试验，以前瞻性地评估这些特定的 PET/CT和液体活检作为检测ICI治疗顽固性肝癌的工具的实施例 β-连环蛋白激活。除了表征和比较FCH PET/CT的预测能力 以及基于第二阶段临床终点的cfDNA突变分析，该项目将利用基于决策树的 机器学习评估综合成像-基因组生物标记物的预测性能 进一步研究肿瘤突变与PET代谢表型和免疫治疗反应的关系。 此外，由于肿瘤对18F-脱氧葡萄糖(FDG)的摄取与肝癌对FCH的摄取不一致，因此 Third Aim将利用这项试验作为分子筛查过程，创建一个丰富的患者亚队列 嗜FDG的肿瘤。这些患者将接受系列FDG PET/CT检查，以评估FDG作为一种预测性来源 肝细胞癌ICI反应的生物标志物。如果发现这些诊断测试 在预测肿瘤耐药性/反应方面可靠，它们可以显著提高临床精确度和 免疫疗法对肝细胞癌和可能的其他癌症的整体益处。