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

• 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
• 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

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.

项目摘要/摘要 黑色素瘤是皮肤癌最致命的形式。它的发病率正在上升，预计有106,000例新病例 美国2021年。免疫检查点抑制剂（ICI）彻底改变了对早期和先进的治疗 黑色素瘤，具有并发抗CTLA-4和抗PD-1单克隆抗体，证明了反应 〜50％的患者，包括高度耐用的反应。不幸的是，没有足够的生物标志物可以预测 对单个代理或组合ICI的响应，以及双重检查点封锁与显着等级有关 约55％的患者中有3/4免疫相关的不良事件（IRAE）。我们的PTRC的目标旨在解决 两个未满足的临床需求：（i）提高我们对ICIS抗性机制设计的理解 有效的免疫疗法和组合，（ii）识别潜在的生物标志物以选择患者 适当地适用于单药与组合免疫疗法并预测和监测IRAE。在我们的 临床前臂，我们将对临床注释的预处理活检进行综合的蛋白质组分析 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反应的现有签名，并进一步阐明机制 ICI响应/抗性和与Iraes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的测定法确认和扩展临床前臂中产生的发现。