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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

基本信息

批准号：
10693135
负责人：
Sandi Alexander Kwee
金额：
$ 58.67万
依托单位：
QUEEN'S MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10693135
关键词：
Biological Markers Cancer Etiology Cells Cessation of life Characteristics Classification Clinical Clinical Trials Communication DNA Sequence Alteration DNA sequencing Decision Trees Detection Diagnostic tests Effectiveness 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 Prediction of Response to Therapy 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 Tumor Subtype United States Woman X-Ray Computed Tomography advanced disease anti-PD-1 antibody inhibitor beta catenin blood-based biomarker cancer therapy cell free DNA checkpoint therapy clinic ready 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 protein 1 programs prospective response screening targeted sequencing tool transcriptomics treatment response tumor tumor DNA tumor microenvironment tumor progression uptake

项目摘要

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.

项目总结/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。