Proteogenomic studies to understand mechanisms and drivers of resistance to immunotherapies

蛋白质组学研究以了解免疫疗法耐药的机制和驱动因素

基本信息

批准号：
10647807
负责人：
Diwakar Davar
金额：
$ 115.69万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-16 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647807
关键词：
Acetylation Address American College of Radiology Imaging Network Bioinformatics Biological Assay Biological Markers Biometry Biopsy Cancer Center Clinical Clinical Chemistry Clinical Data Clinical Trials Combination immunotherapy Data Data Analyses Data Commons Early treatment Eastern Cooperative Oncology Group Environment Formalin Freezing Funding Genomics Goals Immune checkpoint inhibitor Immunologic Monitoring Immunologics Immunotherapeutic agent Immunotherapy Incidence Knowledge Laboratories Malignant Neoplasms Mass Spectrum Analysis Measurement Paraffin Embedding Pathology Pathway interactions Patient Selection Patients Peptides Positioning Attribute Post-Translational Protein Processing Proteins Proteome Proteomics Publications Resistance Running Skin Cancer Southwest Oncology Group Specimen Testing Tissues Toxic effect Training Ubiquitin Validation anti-CTLA4 anti-PD-1 anti-PD1 antibodies arm cancer clinical trial cancer immunotherapy clinical biomarkers cohort design experience immune checkpoint blockade immune-related adverse events immunoregulation immunotherapy trials improved meetings melanoma multiple reaction monitoring potential biomarker pre-clinical predicting response programmed cell death protein 1 prospective proteogenomics resistance mechanism response transcriptome sequencing transcriptomics tumor tumor immunology

项目摘要

Project Summary/Abstract Melanoma is the deadliest form of skin cancer. Its incidence is on the rise with 106,000 new cases expected in the U.S. in 2021. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of early and advanced melanoma, with concurrent anti-CTLA-4 and anti-PD-1 monoclonal antibodies demonstrating a response in ~50% of patients, including highly durable responses. Unfortunately, there are no adequate biomarkers to predict response to single agent or combination ICI, and dual checkpoint blockade is associated with significant grade 3/4 immune-related adverse events (irAEs) in ~55% of patients. The goals of our PTRC are designed to address two unmet clinical needs: (i) improve our understanding of mechanisms of resistance to ICIs to design more effective immunotherapies and combinations, and (ii) identify potential biomarkers to select patients appropriately for single agent vs combination immunotherapies and to predict and monitor irAEs. In our Preclinical Arm, we will perform integrated proteogenomic analysis of clinically annotated, pre-treatment biopsies from melanoma patients who received ICI. The data will be analyzed in the context of clinical annotations to refine an existing signature of melanoma ICI response identified by our team and to further elucidate mechanisms of ICI response/resistance and signatures associated with irAEs. In our Clinical Arm, we will analyze clinical trial biospecimens using MRM-based assays to confirm & extend findings generated in the Preclinical Arm.

项目概要/摘要黑色素瘤是最致命的皮肤癌。其发病率呈上升趋势，预计 2019 年新增病例 106,000 例 2021 年美国。免疫检查点抑制剂 (ICIs) 彻底改变了早期和晚期癌症的治疗黑色素瘤，同时使用抗 CTLA-4 和抗 PD-1 单克隆抗体，显示出对约 50% 的患者，包括高度持久的反应。不幸的是，没有足够的生物标志物来预测对单药或组合 ICI 的反应，双检查点封锁与显着等级相关约 55% 的患者中有 3/4 发生免疫相关不良事件 (irAE)。我们 PTRC 的目标旨在解决两个未满足的临床需求：（i）提高我们对 ICI 耐药机制的理解，以设计更多有效的免疫疗法和组合，以及（ii）识别潜在的生物标志物来选择患者适用于单药与联合免疫疗法以及预测和监测 irAE。在我们的临床前部门，我们将对临床注释的治疗前活检进行综合蛋白质组学分析来自接受 ICI 的黑色素瘤患者。数据将在临床注释的背景下进行分析完善我们团队确定的黑色素瘤 ICI 反应的现有特征并进一步阐明机制 ICI 反应/抵抗以及与 irAE 相关的特征。在我们的临床部门，我们将分析临床试验使用基于 MRM 的检测来确认和扩展临床前组中产生的结果的生物样本。