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: 10437906
• 负责人: Sandi Alexander Kwee
• 金额: $ 23.86万
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437906
• 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 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; diagnostic tool; 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; treatment response; 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（HCC）是全球癌症死亡率的主要原因，其发病率是 在美国，男性和女人都在上升。抗PD1和抗PD-L1免疫检查点抑制剂（ICI） 然而，现在抗体已批准为高级HCC，但是，接收这些药物的患者中只有20％ 将显示对治疗的客观反应。因为免疫相关的不良事件是非平凡的，预测的 需要解释可以解释免疫疗法反应变异性的生物标志物以优化患者选择。 最近的几项研究方案已融合到Wnt/beta-的致癌激活中 Catenin信号通路，具有肿瘤免疫探测和对HCC中ICI治疗的临床反应不佳。在 先前的研究，我们发现HCC表现出高度吸收正电子发射断层扫描 /计算 层析成像（PET/CT）成像剂18F-氟胆碱（FCH）通常属于分子肿瘤亚型 与β-catenin的激活和免疫避免有关。基于靶向测序的液体活检 无细胞的DNA（CFDNA）也使识别具有伴有突变的肿瘤的患者成为可能 与Wnt/beta-catenin信号的增加有关。 该项目包括2阶段生物标志物临床试验，以预期评估这些特定 PET/CT和液体活检的实施例，作为用于根据ICI治疗HCC顽固症的工具 β-catenin激活。除了表征和比较FCH PET/CT的预测能力外 和CFDNA突变分析基于第2阶段的临床终点，该项目将利用基于决策树 机器学习以估计综合成像基因组生物标志物的预测性能 进一步研究肿瘤突变与PET代谢表型和免疫疗法反应如何相关的。 此外，由于肿瘤18F-氟脱氧葡萄糖（FDG）的摄取与HCC中的FCH摄取不一致，A 第三目的将利用该试验作为分子筛查过程 FDG avid肿瘤。这些患者将经历系列FDG PET/CT以评估FDG作为预测的来源 ICI反应的生物标志物对HCC的正交分子亚型。如果找到这些诊断测试 可靠地预测肿瘤抗性/反应，它们可以显着提高临床精度和 免疫疗法对HCC和可能其他癌症的总体好处。